Novel DPP1 inhibitors and their use

Abstract

Disclosed herein are novel DPP1 inhibitor compounds having the general structure of formula (I), (II), or (III), or pharmaceutically acceptable salts thereof. Also provided are specific methods of treatment, such as a method for treating, for example, an obstructive disorder of the airway, or a method for treating an inflammatory condition, using a composition comprising an effective amount of one of the compounds provided herein.

Description

Technical Field

[0001] Dipeptidyl peptidase 1 (DPP1, EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family with a molecular weight of 200 kDa. DPP1 was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851 - 858), but the cDNA of the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326 - 330). DPP1 is the only member of the papain family that functions as a tetramer and consists of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain, and a light chain (Dolenc et al. 1995, J Biol Chem, 270, 21626 - 21631).

Background Art

[0002] DPP1 is constitutively expressed in many tissues, with the highest levels in the lung, kidney, liver, and spleen. DPP1 catalyzes the removal of dipeptides from the N-terminus of polypeptide substrates with broad specificity. Recent data suggest that in addition to being an important enzyme in lysosomal proteolysis, DPP1 also functions as an important enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzyme A and B), mast cells (chymase and tryptase), and neutrophils (cathepsin G, neutrophil elastase, and proteinase-3).

[0003] Mast cells are found in many tissues, but are more numerous along the inner epithelial layer of the body such as the skin, respiratory tract, and gastrointestinal tract. In humans, two types of mast cells have been identified. Type T, which expresses only tryptase, and type MC, which expresses both tryptase and chymase. In humans, type T mast cells are mainly located in alveolar tissue and intestinal mucosa, and type TC cells are abundant in the skin and conjunctiva. Tryptase and chymase are thought to be important mediators of allergic diseases involved in the processes of inflammation, bronchoconstriction, and mucus secretion.

[0004] Neutrophils play an important role in host defense against invading pathogens. Neutrophils are produced in the bone marrow, are released into the circulation fully mature, and assume the role of the first choice for cell defense. Pro-inflammatory mediators and chemotactic attractants activate neutrophils and attract them to the site of infection, where they phagocytose bacteria by phagocytosis and attack them with a stockpile of antibacterial compounds using both oxidative and non-oxidative attack methods. Neutrophil elastase, a powerful serine protease, is one of the antibacterial compounds clearly involved in the destruction of bacteria. Neutrophil elastase is released into the phagolysosome surrounding the microorganism, which advances the microorganism towards destruction. Neutrophil elastase can attack OmpA, an outer membrane protein in Gram-negative bacteria, and not only helps to directly kill the pathogen by degrading its membrane, but also enables other antibacterial compounds to access the pathogen. Furthermore, neutrophil elastase can help to process other antibacterial compounds such as cathelicidin and convert them from their inactive propeptide form to their active state.

[0005] However, neutrophil elastase can also cause problems in the host. It is one of the most destructive enzymes in the body and has the ability to degrade extracellular matrix proteins (including collagen, proteoglycan, fibronectin, platelet receptors, complement receptors, thrombomodulin, pulmonary surfactant, and cadherin) and major plasma proteins (including coagulation factors and complement factors, immunoglobulins, some proteases, and protease inhibitors). Under physiological conditions, endogenous protease inhibitors such as α1 - antitrypsin tightly control the activity of neutrophil elastase. However, at inflammatory sites, neutrophil elastase can evade control, and when control is lost, it can induce the release of pro - inflammatory cytokines such as interleukin - 6 and interleukin - 8, potentially causing acute lung injury. By degrading phagocyte surface receptors and opsonins, it may even impair the host defense against infection. Its negative role is shown by its involvement in tissue destruction and inflammation, which characterize many diseases including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemia - reperfusion injury, and rheumatoid arthritis.

[0006] Therefore, in the art, there is a need to provide novel DPP1 inhibitors for treating the aforementioned diseases, as well as other diseases related to DPP1 and neutrophil elastase.

Summary of the Invention

[0007] In one aspect of the present invention, it is a DPP1 inhibitor compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0008] In another aspect of the present invention, a DPPI inhibitor of formula (I-I), or a pharmaceutically acceptable or deuterated form thereof, is provided, [Chemical formula] , or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 is [Chemical formula] and R 2 is [Chemical formula] and X1, X2, and X3 are independently O, S, NR 3 , or CR 3 R 4 and each R 3 , R 4 , and R 5 is independently H, F, Cl, Br, I, or C1-C6 alkyl, each R 6 is independently H or C1-C6 alkyl, each Y is independently O, S, CHR 6 , or NR 6 and m and m' are each independently an integer from 0 to 3, and the sum of m and m' is ≦3, L is

Chemical formula

Chemical formula

[0009] In another aspect of the present invention, a DPP1 inhibitor of formula (II), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, L is [Chemical formula] as follows.

[0011] In yet another aspect, the DPP1 inhibitor provided herein is a sulfonamide compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein: [Chemical formula] , wherein R 1 is [Chemical formula] as follows, L is [Chemical formula] as follows, each R 2 is independently H, F, Cl, Br, I, or C1-C6 alkyl, and the compound is a pharmaceutically acceptable salt thereof.

[0012] In yet another aspect, the DPP1 inhibitor provided herein is a sulfonamide compound of formula (III), or a pharmaceutically acceptable salt thereof, wherein: [Chemical formula] , wherein R1 is [Chem.] and L is [Chem.] and each R 2 is independently H, F, Cl, Br, I, or C1-C6 alkyl, a compound, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments of the compound of formula (III), R 1 is [Chem.] as such.

[0014] In yet another aspect of the present invention, a method of treatment is provided. In one embodiment, the method of treatment comprises administering to a patient in need of treatment a composition comprising an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt of a compound of formula (I), (II) or (III). In one embodiment of the method, the composition is administered orally. In a further embodiment, the composition is administered orally once a day.

[0015] In one embodiment, the method of treatment is a method of treating an obstructive airway disease, such as cystic fibrosis (CF), asthma, or bronchiectasis (e.g., non-CF bronchiectasis).

[0016] In another embodiment, the method of treatment is a method of treating chronic rhinosinusitis (CRS). In yet another embodiment, the method of treatment is a method of treating. BRIEF DESCRIPTION OF THE DRAWINGS

[0017]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Mode for Carrying Out the Invention

[0018] The term "alkyl", unless otherwise specified, includes both straight-chain and branched-chain alkyl groups, which may be substituted or unsubstituted. Examples of "alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, and pentyl.

[0019] The term "pharmaceutically acceptable", unless otherwise specified, is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being suitable for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any harmful effects that the moiety may have. Harmful effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0020] Formula (I) In one aspect of the present invention, a DPP1 inhibitor compound is provided. In one embodiment of this aspect, a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0021] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

[0022] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

[0023] In another embodiment of the compound of formula (I), R 1 is

Chem.

[0024] In yet another embodiment of the compound of formula (I), R 1 is

Chem.

[0025] In yet another embodiment of the compound of formula (I), R 1 is

Chem.

[0026] In yet another embodiment of the compound of formula (I), R 1 is

Chem.

[0027] In yet another embodiment of the compound of formula (I), R 1 is

Chem.

[0028] Yet another embodiment of the compound of formula (I) is provided, and the compound of formula (I) is a compound of formula (IA), (IB), (IC), (ID), or a pharmaceutically acceptable salt or deuterated form of one of the foregoing. For the compounds of formula (IA), (IB), (IC), (ID), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is defined as in formula (I).

Chem.

[0029] In one embodiment of the compound of formula (I), the compound of formula (I) is a compound of formula (I-I)

Chem.

Chem.

Chem.

Chem.

Chem.

[0030] Another embodiment of the compound of formula (I-I) is provided, and the compound of formula (I-I) is a compound of formula (IA-I), (IB-I), (IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form of one of the foregoing. For the compound of formula (IA-I), (IB-I), (IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form thereof, m', m, L, X 1 , R 2 , and R 5 are defined as in formula (I-I).

Chem.

[0031] R 1 is

Chem.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

[0032] In one embodiment, R 1 is

Chem.

[0033] In one embodiment, R 1 is

Chem.

[0034] In one embodiment, R 1 is

Chemical formula

[0035] In one embodiment of formula (I), R 1 is

Chemical formula

[0036] In another embodiment of formula (I), R 1 is

Chemical formula

Table 2

[0037] In some embodiments of formula (I), X1 is O.

[0038] In some embodiments of formula (I), X1 is S.

[0039] In some embodiments of formula (I), X1 is NH.

[0040] In some embodiments of formula (I), X1 is CH2.

[0041] In some embodiments of formula (I), R 2 is [Chemical formula] is as follows.

[0042] In one embodiment of formula (I), R 2 is [Chemical formula] is as follows.

[0043] In some embodiments of formula (I), R 2 is [Chemical formula] is as follows.

[0044] In another embodiment of formula (I), R 2 is [Chemical formula] is as follows.

[0045] In some embodiments of formula (I), R 2 is [Chemical formula] is as follows.

[0046] In yet another embodiment of formula (I), R 2 is [Chemical formula] is as follows.

[0047] In a plurality of embodiments of formula (I), R 2 is [Chemical formula] is as follows.

[0048] In some embodiments of formula (I), R 2 is

Chem.

[0049] In another embodiment of formula (I), R 2 is

Chem.

[0050] In another embodiment of formula (I), R 2 is

Chem.

[0051] In some embodiments of formula (I), R 2 is

Chem.

[0052] In yet another embodiment of formula (I), R 2 is

Chem.

[0053] In another embodiment of formula (I), R 2 is [Chemical formula] is. In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is -CH3.

[0054] In some embodiments of formula (I), L is [Chemical formula] is.

[0055] In some embodiments of formula (I), L is [Chemical formula] is.

[0056] In another embodiment of formula (I), L is [Chemical formula] is.

[0057] In yet another embodiment of formula (I), L is [Chemical formula] is. In some embodiments, each R 5 is H. In some embodiments, at least one R 5 is halogen (e.g., F, Cl, Br, or I). In some embodiments, at least one R 5 is F. In some embodiments, at least two R 5 are F.

[0058] In some embodiments of formula (I), L is [Chemical formula] is as follows.

[0059] In some embodiments of formula (I), L is

Chemical formula

[0060] In some embodiments of formula (I), L is

Chemical formula

[0061] In some embodiments of formula (I), L is

Chemical formula

[0062] In some embodiments of formula (I), L is

Chemical formula

[0063] In some embodiments of formula (I), L is

Chemical formula

[0064] In other embodiments of formula (I), L is

Chemical formula

Chemical formula

[0065] In some embodiments of formula (I), L is

Chemical formula

Chemical formula

[0066] Table 3 provides other exemplary embodiments of the compounds of formula (I). It should be noted that, similar to other things disclosed herein, these compounds can also be provided as pharmaceutically acceptable salts or deuterated forms.

Table 3-1

Table 3-2

Table 3-3

Table 3-4

[0067] In another aspect of the present invention, the DPP1 inhibitor of formula (I), for example, the compounds of formula (I-I), (IA), (IB), (IC), (ID), (IE), (I-I), (IA-I), (IB-I), (IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form thereof is one or more compounds selected from Table 4.

Table 4-1

Table 4-2

Table 4-3

Table 4-4

[0068] In another aspect of the present invention, the DPP1 inhibitor of formula (I), for example, the compounds of formula (I-I), (IA), (IB), (IC), (ID), (I-E), (I-I), (IA-I), (IB-I), (IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form thereof, is one or more compounds selected from Table 5.

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

Table 5-6

[0069] In another aspect of the present invention, the DPP1 inhibitor of formula (I), for example, the compounds of formula (I-I), (IA), (IB), (IC), (ID), (IE), (I-I), (IA-I), (IB-I), (IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form thereof, is one or more compounds selected from Table 6.

Table 6-1

Table 6-2

Table 6-3

[0070] In another aspect of the present invention, the DPP1 inhibitor of formula (I), for example, the compounds of formula (I-I), (IA), (IB), (IC), (ID), (IE), (I-I), (IA-I), (IB-I), IC-I), (ID-I), or a pharmaceutically acceptable salt or deuterated form thereof, is one or more compounds selected from Table 7.

Table 7-1

Table 7-2

Table 7-3

Table 7-4

Table 7-5

Table 7-6

[0071] Formula (II) In another aspect of the present invention, a DPP1 inhibitor of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, wherein:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0072] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0073] In another embodiment of the compound of formula (II), R 1 is

Chemical formula

Chemical formula

[0074] In yet another embodiment of the compound of formula (II), R 1 is

Chemical formula

Chemical formula

[0075] In yet another embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0076] In yet another embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0077] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0078] In yet another embodiment of the compound of formula (II), R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0079] In yet another embodiment of the compound of formula (II), R 1 is

Chemical formula

Chemical formula

[0080] In another embodiment of the compound of formula (II), R 1 is

Chemical formula

Chemical formula

[0081] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0082] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0083] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0084] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0085] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0086] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R2 is [Chem.] as follows.

[0087] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] as follows. In a further embodiment, R 2 is [Chem.] as follows.

[0088] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] as follows. In a further embodiment, R 2 is [Chem.] as follows.

[0089] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] as follows. In a further embodiment, R 2 is [Chem.] as follows.

[0090] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0091] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0092] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0093] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0094] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0095] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0096] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0097] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0098] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0099] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0100] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0101] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is

Chem.

[0102] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0103] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0104] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0105] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0106] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0107] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0108] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0109] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0110] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0111] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0112] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

[0113] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0114] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0115] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is as follows. In a further embodiment, R 2 is [Chemical formula] is as follows.

[0116] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is

Chemical formula

[0117] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0118] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0119] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0120] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0121] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0122] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0123] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chem.] . In a further embodiment, R 2 is [Chem.] .

[0124] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0125] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0126] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0127] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 1 is

Chemical formula

[0128] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemistry] is. In a further embodiment, R 2 is [Chemistry] is.

[0129] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemistry] is. In a further embodiment, R 2 is [Chemistry] is.

[0130] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemistry] is. In a further embodiment, R 2 is [Chemistry] is.

[0131] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemistry] is. In a further embodiment, R 2 is [Chemical formula] is.

[0132] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0133] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0134] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0135] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0136] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0137] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 1 is

Chem.

Chem.

[0138] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0139] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0140] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0141] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0142] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chem.

[0143] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0144] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0145] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, R 1 is

Chem.

Chem.

[0146] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0147] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0148] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0149] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is [Chemical formula] is. In a further embodiment, R 2 is [Chemical formula] is.

[0150] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0151] In one embodiment of the compound of formula (II), L is

Chem.

Chem.

[0152] In one embodiment of the compound of formula (II), L is one of the following:

Chem.

[0153] In one embodiment of the compound of formula (II), L is

Chem.

Chem.

Chem.

[0154] In one embodiment of the compound of formula (II), L is one of the following:

Chem.

[0155] In an embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, the compound is one or more selected from Table 8.

Table 8-1

Table 8-2

Table 8-3

Table 8-4

Table 8-5

[0156] In an embodiment of the compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, the compound is one or more selected from Table 9.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 9-5

Table 9-6

Table 9-7

Table 9-8

Table 9-9

Table 9-10

Table 9-11

Table 9-12

[0157] Formula (III) In yet another aspect, the DPP1 inhibitors provided herein are sulfonamide compounds of Formula (III), or pharmaceutically acceptable salts or deuterated forms thereof, wherein:

Chemical Structure

Chemical Structure

Chemical Structure

[0158] In one embodiment of the compound of Formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical Structure

Chemical Structure

[0159] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0160] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0161] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0162] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chem.

[0163] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0164] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0165] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chem.

[0166] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chem.

Chemical formula

[0167] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0168] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0169] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0170] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0171] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, R 1 is

Chemical formula

Chemical formula

[0172] In one embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, L is

Chemical formula

Chemical formula

Chemical formula

[0173] In an embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, the compound is one or more selected from Table 10.

Table 10

[0174] In an embodiment of the compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, the compound is one or more selected from Table 11.

Table 11-1

Table 11-2

Table 11-3

Table 11-4

Table 12-1

Table 12-2

Table 12-3

[0175] In some embodiments, the present disclosure provides a compound having the following chemical formula:

Chem.

[0176] In some embodiments, the present disclosure provides a compound having the following chemical formula:

Chem.

[0177] In one embodiment, certain compounds of formula (I), (II), and / or (III) can exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers. While the preferred forms of the compounds of formula (I), (II), and (III) have either S (one chiral center) or, in the case of two chiral centers, S,S stereochemistry, it should be understood that the present disclosure encompasses all such isomeric forms. For example, regardless of R 1 the skeletons of the compounds of formula (I) and (II) have two chiral centers in some embodiments. For the compounds of the present invention, chiral center 1 is a substituted carbon atom to which a cyano group, -NH-, and -CH2- group are attached. In a preferred embodiment, the present disclosure encompasses compounds of the present invention having an (S) configuration at chiral center 1. However, in another embodiment, the compounds disclosed herein have an (R) configuration at chiral center 1. Chiral center 2 is the carbon atom of an R 1 group attached to a CO group in certain compounds disclosed herein, such as compounds of formula (I) and / or (II). The present disclosure encompasses compounds of the present invention having an (S) configuration at chiral center 2 and compounds of the present invention having an (R) configuration at chiral center 2, with the (S) configuration being preferred.

[0178] If the acid or base co-former is a solid at room temperature and there is no proton transfer or only partial proton transfer between the compound of formula (I), (II), or (III) and such an acid or base co-former, a co-crystal of the co-former and the compound of formula (I), (II), or (III) can form instead of a salt. All such co-crystalline forms of the compound of formula (I), (II), or (III) are encompassed by the present disclosure. The compound of formula (I), (II), or (III) can form a mixture of its salt and co-crystalline form. It should also be understood that the present disclosure encompasses salt / co-crystal mixtures of the compound of formula (I), (II), or (III).

[0179] Salts and co-crystals can be characterized using well-known techniques such as X-ray powder diffraction, single-crystal X-ray diffraction (e.g., to evaluate proton positions, bond distances, or bond angles), solid-state NMR (e.g., to evaluate C, N, or P chemical shifts), or spectroscopic techniques (e.g., to measure O-H, N-H, or COOH signals and IR peak shifts arising from hydrogen bonding).

[0180] It should also be understood that certain compounds of formula (I), (II), or (III) may exist in solvated forms, such as hydrates, including solvates of pharmaceutically acceptable salts of the compounds of formula (I), (II), or (III).

[0181] Certain compounds of formula (I), (II), or (III) may also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted with respect to that particular linkage (e.g., restrictions arising from the presence of a ring bond or double bond). Thus, it should be understood that the present disclosure encompasses all such isomers. Certain compounds of formula (I), (II), or (III) may also contain multiple tautomeric forms. It should be understood that the present disclosure encompasses all such tautomeric forms. Stereoisomers may be separated using conventional techniques such as chromatography or fractional crystallization, or stereoisomers may be prepared by stereoselective synthesis.

[0182] In a further embodiment, the compounds of formula (I), (II), or (III) include any isotope-labeled (or radiolabeled) derivatives of the compounds of formula (I), (II), or (III). Such derivatives are derivatives of the compounds of formula (I), (II), or (III) in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that can be incorporated include 2H (also represented as "D" for deuterium).

[0183] In a further embodiment, the compound of formula (I), (II), or (III) may be administered in the form of a prodrug that is decomposed in the human or animal body to yield the compound of formula (I), (II), or (III). Examples of prodrugs include in vivo hydrolyzable esters of the compounds of formula (I), (II), or (III).

[0184] In vivo hydrolyzable (or cleavable) esters of the compounds of formula (I), (II), or (III) containing a carboxy group or a hydroxy group are pharmaceutically acceptable esters that are hydrolyzed, for example, in the human or animal body to produce the parent acid or alcohol. For examples of ester prodrug derivatives, see, for example, Curr. Drug. Metab. 2003, 4, 461. Various other forms of prodrugs are known in the art. See, for example, Nature Reviews Drug Discovery 2008, 7, 255 and the references cited therein.

[0185] The compounds provided herein can be synthesized by various synthetic routes, and the ultimate choice of route depends on R 1 , L, and R 2 substituents, and certain routes may also require additional protecting group strategies. One such route involves initial stage Burgess dehydration of a suitable N-Boc protected "L" starting material, followed by preparation of an "L-R 2 " intermediate by Suzuki coupling, and subsequent N-Boc deprotection and amide bond coupling to the appropriate R 1 moiety to obtain the final compound.

[0186] Another synthetic route begins with the preparation of a formamide "L-R 2 " intermediate by Suzuki coupling, followed by preparation of a formamide derivative by N-Boc deprotection and amide bond formation, which is then subjected to late stage Burgess dehydration to obtain the compounds of the present invention.

[0187] The synthetic routes disclosed in PCT Publication Nos. 2015 / 110826, 2022 / 042591, and Banerjee et al. (2021). Bioorganic & Medicinal Chemistry Letters 47, 128202 (each disclosure of which is incorporated herein by reference in its entirety) can also be used in the present invention.

[0188] The synthetic routes of the various compounds of the present invention are also provided in the Examples section of this specification.

[0189] The compounds of formulas (I), (II), and (III), and their pharmaceutically acceptable salts are DPP1 inhibitors and can therefore be used in any disease area in which DPP1 plays a role. Thus, in one aspect of the present invention, a method of treatment is provided. In one embodiment, the method of treatment comprises administering to a patient in need thereof a composition comprising an effective amount of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt of a compound of formula (I), (II) or (III). The composition is administered to the patient over a period of administration.

[0190] As used herein, the terms "treat", "treating", or "ameliorate" are used interchangeably. These terms refer to an approach for obtaining beneficial or desirable results, including but not limited to therapeutic and / or prophylactic benefits. A therapeutic benefit refers to any therapeutically relevant improvement or effect on one or more diseases, conditions, or symptoms being treated. In one embodiment, the term "treating" includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder, or disease state that a patient is suffering from or is at risk of suffering from, but has not yet experienced or manifested clinically or subclinically, (2) inhibiting a condition, disorder, or disease state (e.g., halting, reducing, or delaying the progression of the disease, or in the case of maintenance therapy, halting, reducing, or delaying its recurrence, with respect to at least one of its clinical or subclinical symptoms), and (3) alleviating a disease state (e.g., by effecting regression or reducing the severity of a condition, disorder, or disease state, or at least one of its clinical or subclinical symptoms).

[0191] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to, for example, produce a beneficial or desired result. The therapeutically effective amount can vary depending on one or more of the subject being treated and the disease state, the subject's weight and age, the severity of the disease state, the method of administration, and the like.

[0192] As used herein, the terms "subject", "individual", and "patient" are used interchangeably to refer to vertebrates such as mammals. Mammals can be, for example, mice, rats, rabbits, cats, dogs, pigs, sheep, horses, non-human primates (e.g., cynomolgus monkeys, chimpanzees), or humans. Also included are tissues, cells, or derivatives thereof of a subject obtained in vivo or cultured in vitro. A human subject can be an adult, adolescent, pediatric (2 - 14 years old), infant (1 - 24 months old), or neonate (up to 1 month old). In some embodiments, an adult is an elderly person about 65 years old or older, or about 60 years old or older.

[0193] For example, in one embodiment, a compound of the invention is administered to a patient in a method for treating an obstructive disorder of the airway. In one embodiment, the obstructive disorder of the airway is asthma (e.g., including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced asthma, and dust-induced asthma, both intermittent and persistent, and of all severities), airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis (e.g., infectious bronchitis, eosinophilic bronchitis), emphysema, cystic fibrosis (CF), bronchiectasis (e.g., non-CF bronchiectasis (NCFBE) and bronchiectasis associated with CF), cystic fibrosis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis (including idiopathic pulmonary fibrosis, acute fibrinous alveolitis, idiopathic interstitial pneumonia, fibrosis associated with anti-tumor therapy and chronic infections (including tuberculosis and aspergillosis and other fungal infections)), complications of lung transplantation, vascular disorders and thrombotic disorders of the pulmonary vasculature, pulmonary hypertension (e.g., pulmonary arterial hypertension), pulmonary hypertension due to left heart disease, pulmonary hypertension associated with chronic lung disease, antitussive activity including the treatment of chronic cough associated with inflammatory and secretory conditions of the airway, iatrogenic cough, drug-induced rhinitis, and acute and chronic rhinitis including vasomotor rhinitis, and perennial and seasonal allergic rhinitis (hay fever) including allergic rhinitis, nasal polyps, acute viral infections including the common cold, and infections caused by respiratory viruses (e.g., respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus), acute lung injury, acute respiratory distress syndrome (ARDS), and exacerbations of each of the aforementioned respiratory airway disease states.

[0194] In one embodiment, a compound of the invention is administered to a patient in a method for treating heart failure. In one embodiment, the heart failure is heart failure with preserved ejection fraction or heart failure. In another embodiment, the heart failure is heart failure with reduced ejection fraction.

[0195] Cystic fibrosis (CF) is caused by abnormalities in the cystic fibrosis transmembrane conductance regulator protein, leading to chronic lung infections (especially by Pseudomonas aeruginosa) and excessive inflammation, resulting in bronchiectasis, reduced lung function, respiratory failure, and a poor quality of life. The inflammatory process is dominated by neutrophils that produce NE, as well as other destructive NSPs including CatG and PR3 that act directly on extracellular matrix proteins and play a role in the host response to inflammation and infection (Dittrich et al., Eur Respir J. 2018;51(3)). The methods provided herein use reversible inhibitors of DPP1. Without wishing to be bound by theory, the compounds of formula (I), (II), or (III) administered via the methods provided herein have beneficial effects by inhibiting the activation of NSPs and reducing inflammation, which in turn is thought to result in a decrease in pulmonary exacerbations, a decrease in the rate of pulmonary exacerbations, and / or an improvement in lung function (e.g., forced expiratory volume in 1 second [FEV1]) in CF patients.

[0196] In one embodiment, a method for treating CF is provided, the method comprising administering to a patient in need of treatment for CF a composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof. Routes of administration include oral administration. The dosing schedule and duration of administration can be determined by the user of the method, e.g., a prescribing physician. In one embodiment, the administration is once daily. In another embodiment, the administration is twice daily. In another embodiment, the administration is every other day, every three days, three times a week, or four times a week.

[0197] In one of the methods for treating CF, a composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment for CF over a period of administration. The method comprises improving the patient's lung function during the period of administration as compared to the patient's lung function prior to the period of administration. In a further embodiment, the composition is administered orally once daily. In one embodiment, the improvement in lung function is measured by spirometry.

[0198] In one embodiment, improving the patient's lung function includes increasing the patient's forced expiratory volume in one second (FEV1), increasing the patient's forced vital capacity (FVC), increasing the patient's peak expiratory flow rate (PEFR), or increasing the patient's forced expiratory flow at 25% to 75% of FVC (FEF (25-75%) ). Increasing can be, in one embodiment, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% of each value. Increasing can be, in one embodiment, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In yet another embodiment, increasing is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20%. In yet another embodiment, increasing is about 10% to about 50%, about 15% to about 50%, about 20% to about 50%, or about 25% to about 50%.

[0199] In one embodiment of the method provided herein, a composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, is administered over a period of time to a patient with bronchiectasis in need of treatment. Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. Symptoms vary from intermittent coughing up and episodes of infection localized to the affected lung regions to frequent daily persistent coughing up of large amounts of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as airway damage resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), which is hereby incorporated by reference in its entirety for all purposes).

[0200] Bronchiectasis is considered a pathological endpoint resulting from many disease processes and is a persistent or progressive condition characterized by dilated thick-walled bronchi. Symptoms vary from intermittent coughing up and episodes of infection localized to the affected lung regions to frequent daily persistent coughing up of large amounts of purulent sputum. Bronchiectasis may be associated with other non-specific respiratory symptoms. Without wishing to be bound by theory, the pathological process underlying bronchiectasis has been reported as airway damage resulting from an event or series of events in which inflammation is central to the process (Guideline for non-CF Bronchiectasis, Thorax, July 2010, V.65(Suppl 1), which is hereby incorporated by reference in its entirety for all purposes).

[0201] The methods provided herein use reversible inhibitors of DPP1. Without wishing to be bound by theory, the compounds of formula (I), (II), or (III) administered via the methods provided herein have beneficial effects by reducing inflammation and mucus hypersecretion, and in some embodiments, this is thought to result in a reduction in pulmonary exacerbations, a reduction in the rate of pulmonary exacerbations, and / or an improvement in lung function (e.g., cough, sputum production, forced expiratory volume in 1 second [FEV1]) in patients with bronchiectasis. Without wishing to be bound by theory, the methods provided herein are thought to modify the progression of bronchiectasis by reducing the rate of decline in lung function or the accelerated rate of lung tissue destruction.

[0202] In one embodiment, the bronchiectasis is non-CF bronchiectasis.

[0203] In one embodiment, a method for treating bronchiectasis comprises improving the lung function of a patient during an administration period as compared to the lung function of the patient before the administration period.

[0204] In one embodiment, a pulmonary exacerbation is characterized by three or more of the following symptoms presented by a patient for at least 48 hours: (1) an increase in cough, (2) an increase in sputum volume or a change in sputum viscosity, (3) an increase in sputum purulence, (4) an increase in shortness of breath and / or a decrease in exercise tolerance, (5) fatigue and / or malaise, (6) hemoptysis. In a further embodiment, the three or more symptoms result in a decision by a physician to prescribe an antibiotic to the patient presenting the symptoms.

[0205] In one embodiment of a method for treating bronchiectasis, the method comprises reducing the rate of pulmonary exacerbation in a subject as compared to the rate of pulmonary exacerbation experienced by the subject prior to the administration period of the composition, or as compared to a control subject having bronchiectasis who is not the subject of the treatment method. In a further embodiment, the bronchiectasis is non-CF bronchiectasis.

[0206] In another aspect, a method for treating chronic rhinosinusitis (CRS) is provided in a subject in need thereof. The method, in one embodiment, comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, over a period of administration.

[0207] Chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP), or chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP). In some embodiments, chronic rhinosinusitis is refractory chronic rhinosinusitis. In some embodiments, refractory chronic rhinosinusitis is refractory chronic rhinosinusitis without nasal polyps (CRSsNP). In some embodiments, refractory chronic rhinosinusitis is refractory chronic rhinosinusitis with nasal polyps (CRSwNP).

[0208] In some embodiments, the subject exhibits one or more symptoms of CRS. In some embodiments, one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) nasal discharge, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent secretions, (l) middle meatus obstruction, (m) mucosal changes in the middle meatus natural ostium route and paranasal sinuses, (n) rhinorrhea, or (o) any combination thereof. In some embodiments, the obstruction of the middle meatus is mucosal obstruction, edematous obstruction, or a combination thereof.

[0209] In some embodiments, administration of the pharmaceutical composition reduces, alleviates the severity of, delays the onset of, or eliminates one or more symptoms of CRS. In some embodiments, one or more symptoms of CRS are (a) nasal congestion, (b) nasal obstruction, (c) rhinorrhea, (d) postnasal drip, (e) facial pressure, (f) facial pain, (g) facial fullness, (h) reduced sense of smell, (i) depression, (j) mucosal edema, (k) mucopurulent discharge, (l) middle meatal obstruction, (m) mucosal changes in the middle meatal natural ostium route and in the paranasal sinuses, (n) nasal discharge, (o) or any combination thereof. In some embodiments, administration of the pharmaceutical composition enhances paranasal sinus drainage.

[0210] In some embodiments, the method comprises reducing a composite severity score of one or more symptoms of CRS. As used herein, "composite severity score" is a quantitative measure of the symptoms of CRS presented by a subject. In some embodiments, the composite severity score is the sum of all daily symptoms exhibited by the subject. In some embodiments, the composite severity score is reduced during or after the administration period as compared to the composite severity score measured prior to the administration period. In some embodiments, one or more symptoms of CRS presented by the subject may be any symptom described herein or known in the art to be associated with CRS. In some embodiments, one or more symptoms of CRS are nasal congestion, reduced sense of smell, nasal discharge, or any combination thereof. In some embodiments, the nasal discharge is anterior rhinorrhea. In some embodiments, the nasal discharge is postnasal drip.

[0211] In some embodiments, the method comprises reducing a subject's Sino-Nasal Outcome Test-22 (SNOT-22) score during or after an administration period as compared to the subject's SNOT-22 score prior to the administration period. As used herein, "SNOT-22" is a patient-reported outcome measure developed for use in CRS, regardless of the presence or absence of nasal polyps, and includes 22 individual questions. The questions target a wide range of issues related to health and health-related quality of life, such as physical problems, functional limitations, and emotional impacts. The theoretical range of the SNOT-22 score is 0-110, with lower scores indicating better health-related quality of life. Further details of the SNOT-22 are provided in Hopkins, et al., Clin. Otolaryngol. 2009, 34, 447-454, and Kennedy, et al., Ann Allergy Asthma Immunol. 2013 October;111(4):246-251, the contents of which are incorporated herein by reference in their entirety.

[0212] Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory disorder. Symptoms often include skin lesions that are associated hair follicles and can be painful, inflamed, and / or swollen. In some cases, when the skin lesions heal, they can recur and result in subcutaneous tunnels and progressive scarring. Because HS is a chronic condition, it persists for years, can worsen over time, and can have a profound impact on quality of life, physical and emotional well-being. In fact, HS patients have an increased rate of anxiety and depression and a suicide risk that is 2.5 times that of the general population.

[0213] Patients with HS are classified according to the severity of the disease, termed the Hurley stage, as mild (stage I), moderate (stage II), or severe (stage III). More than 200,000 cases of HS are diagnosed in the United States each year, but the disease can be difficult to diagnose and requires specialized treatment. HS can be misdiagnosed as an infection, an ingrown hair, or other conditions. Furthermore, current treatment options are limited and lack efficacy.

[0214] In one aspect, a method of treating HS is provided in a subject in need thereof. The method, in one embodiment, comprises administering to the subject a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, over a period of administration. In a further embodiment, the method of treating HS comprises reducing neutrophilic inflammation in the subject.

[0215] In one embodiment, the HS is Hurley stage I HS, Hurley stage II HS, or Hurley stage III HS. In some embodiments, the HS is Hurley stage I HS. In some embodiments, the HS is Hurley stage II HS. In some embodiments, the HS is Hurley stage III HS.

[0216] The present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein over a period of administration. The present disclosure provides a method of treating cancer-induced pain in a subject having cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein over a period of administration. In some embodiments, the cancer-induced pain is cancer-induced bone pain. The present disclosure also provides a method of treating cancer-induced bone pain in a subject having cancer, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of any one of the compounds disclosed herein over a period of administration.

[0217] In some embodiments, the cancer includes a primary solid tumor. In some embodiments, the cancer is selected from the group consisting of bladder cancer, lung cancer, brain cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, liver cancer, hepatocellular carcinoma, kidney cancer, stomach cancer, skin cancer, fibroid cancer, lymphoma, virus-induced cancer, hypopharyngeal cancer, testicular cancer, thymic cancer, thyroid cancer, melanoma, and bone cancer.

[0218] In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is stomach cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is fibroid cancer. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is virus-induced cancer. In some embodiments, the cancer is hypopharyngeal cancer. In some embodiments, the cancer is testicular cancer. In some embodiments, the cancer is thymic cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is bone cancer. In some embodiments, the fibroid cancer is leiomyosarcoma.

[0219] In some embodiments, breast cancer includes ductal carcinoma, lobular carcinoma, medullary carcinoma, colloid carcinoma, tubular carcinoma, or inflammatory breast cancer. In some embodiments, breast cancer includes ductal carcinoma. In some embodiments, breast cancer includes lobular carcinoma. In some embodiments, breast cancer includes medullary carcinoma. In some embodiments, breast cancer includes colloid carcinoma. In some embodiments, breast cancer includes tubular carcinoma. In some embodiments, breast cancer includes inflammatory breast cancer.

[0220] In some embodiments, breast cancer is triple-negative breast cancer. In some embodiments, breast cancer does not respond to hormonal therapy or therapeutic agents targeting the HER2 protein receptor.

[0221] In some embodiments, lymphoma is Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, natural killer cell lymphoma, T-cell lymphoma, Burkitt lymphoma, or Kaposi sarcoma. In some embodiments, lymphoma is Hodgkin lymphoma. In some embodiments, lymphoma is non-Hodgkin lymphoma. In some embodiments, lymphoma is diffuse large B-cell lymphoma. In some embodiments, lymphoma is B-cell immunoblastic lymphoma. In some embodiments, lymphoma is natural killer cell lymphoma. In some embodiments, lymphoma is T-cell lymphoma. In some embodiments, lymphoma is Burkitt lymphoma. In some embodiments, lymphoma is Kaposi sarcoma.

[0222] In some embodiments, the brain cancer is astrocytoma, anaplastic astrocytoma, glioblastoma multiforme, oligodendroglioma, ependymoma, meningioma, schwannoma, or medulloblastoma. In some embodiments, the brain cancer is astrocytoma. In some embodiments, the brain cancer is anaplastic astrocytoma. In some embodiments, the brain tumor is glioblastoma multiforme. In some embodiments, the brain cancer is oligodendroglioma. In some embodiments, the brain tumor is ependymoma. In some embodiments, the brain cancer is meningioma. In some embodiments, the brain cancer is schwannoma. In some embodiments, the brain cancer is medulloblastoma.

[0223] In some embodiments, the cancer is a liquid tumor. In some embodiments, the liquid tumor is selected from the group consisting of acute myeloid leukemia (AML), acute lymphoblastic leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, natural killer cell leukemia, blastic plasmacytoid dendritic cell neoplasm, chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS). In some embodiments, the liquid tumor is acute myeloid leukemia (AML). In some embodiments, the liquid tumor is acute lymphoblastic leukemia. In some embodiments, the liquid tumor is acute lymphocytic leukemia. In some embodiments, the liquid tumor is acute promyelocytic leukemia. In some embodiments, the liquid tumor is chronic myeloid leukemia. In some embodiments, the liquid tumor is hairy cell leukemia. In some embodiments, the liquid tumor is myeloproliferative disorder. In some embodiments, the liquid tumor is natural killer cell leukemia. In some embodiments, the liquid tumor is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the liquid tumor is chronic myelogenous leukemia (CML). In some embodiments, the liquid tumor is mastocytosis. In some embodiments, the liquid tumor is chronic lymphocytic leukemia (CLL). In some embodiments, the liquid tumor is multiple myeloma (MM). In some embodiments, the liquid tumor is myelodysplastic syndrome (MDS).

[0224] In some embodiments, the cancer is a pediatric cancer. In some embodiments, the pediatric cancer is neuroblastoma, Wilms tumor, rhabdomyosarcoma, retinoblastoma, osteosarcoma, or Ewing sarcoma. In some embodiments, the pediatric cancer is neuroblastoma. In some embodiments, the pediatric cancer is Wilms tumor. In some embodiments, the pediatric cancer is rhabdomyosarcoma. In some embodiments, the pediatric cancer is retinoblastoma. In some embodiments, the pediatric cancer is osteosarcoma. In some embodiments, the pediatric cancer is Ewing sarcoma.

[0225] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the subject is at risk of developing metastatic cancer. In some embodiments, the metastatic cancer includes metastases of breast cancer to the brain, bone, pancreas, lymph nodes, and / or liver. In some embodiments, the metastatic cancer includes metastases of bone cancer to the lung. In some embodiments, the metastatic cancer includes metastases of colorectal cancer to the peritoneum, pancreas, stomach, lung, liver, kidney, and / or spleen. In some embodiments, the metastatic cancer includes metastases of gastric cancer to the mesentery, spleen, pancreas, lung, liver, adrenal gland, and / or ovary. In some embodiments, the metastatic cancer includes metastases of leukemia to the lymph nodes, lung, liver, hind limb, brain, kidney, and / or spleen. In some embodiments, the metastatic cancer includes metastases of liver cancer to the intestine, spleen, pancreas, stomach, lung, and / or kidney. In some embodiments, the metastatic cancer includes metastases of lymphoma to the kidney, ovary, liver, bladder, and / or spleen.

[0226] In some embodiments, metastatic cancer includes metastasis of hematopoietic cancer to the intestine, lung, liver, spleen, kidney, and / or stomach. In some embodiments, metastatic cancer includes metastasis of melanoma to the lymph nodes and / or lung. In some embodiments, metastatic cancer includes metastasis of pancreatic cancer to the mesentery, ovary, kidney, spleen, lymph nodes, stomach, and / or liver. In some embodiments, metastatic cancer includes metastasis of prostate cancer to the lung, pancreas, kidney, spleen, intestine, liver, bone, and / or lymph nodes. In some embodiments, metastatic cancer includes metastasis of ovarian cancer to the diaphragm, liver, intestine, stomach, lung, pancreas, spleen, kidney, lymph nodes, and / or uterus. In some embodiments, metastatic cancer includes metastasis of multiple myeloma to bone.

[0227] In some embodiments, metastatic cancer includes metastasis of lung cancer to the bone, brain, lymph nodes, liver, ovary, and / or intestine. In some embodiments, metastatic cancer includes metastasis of kidney cancer to the liver, lung, pancreas, stomach, brain, and / or spleen. In some embodiments, metastatic cancer includes metastasis of bladder cancer to the bone, liver, and / or lung. In some embodiments, metastatic cancer includes metastasis of thyroid cancer to the bone, liver, and / or lung.

[0228] In some embodiments, the methods disclosed herein include treating cancer-induced bone pain (CIBP) in a subject having cancer metastases to bone. In some embodiments, the subject has metastases to bone from prostate cancer, breast cancer, lung cancer, or myeloma. In some embodiments, the subject is identified as having metastases to bone by using any one of the following methods: plain film radiography, computed tomography, technetium 99m bone scan, magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, fluorine positron emission tomography, and / or choline positron emission tomography, and has not yet experienced cancer-induced bone pain. In some embodiments, the subject is suffering from cancer-induced bone pain, which indicates metastases to bone of a previously treated or untreated primary tumor. In some embodiments, the cancer has metastasized to the vertebrae, pelvis, long bones, or ribs.

[0229] In some embodiments, administration of the composition reduces the severity of cancer, delays the onset of cancer, or eliminates the symptoms of cancer. In some embodiments, the symptoms of cancer are cancer-induced bone pain (CIBP). In some embodiments, CIBP is neuropathic pain. In some embodiments, CIBP is inflammatory pain. In some embodiments, CIBP is spontaneous pain. In some embodiments, the symptoms of cancer are nociceptive hypersensitivity. In some embodiments, the symptoms of cancer are allodynia. In some embodiments, the allodynia is contact allodynia. In some embodiments, the contact allodynia is static mechanical allodynia. In some embodiments, the contact allodynia is dynamic mechanical allodynia. In some embodiments, the subject has bone cancer or metastases to bone.

[0230] In yet another embodiment of the present invention, there is provided a method for treating lupus nephritis (LN) in a subject in need thereof. The method comprises administering to the subject, over a period of administration, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0231] Rheumatoid arthritis (RA) is characterized by inflammation and thickening of the joint capsule, along with effects on the underlying bone and cartilage. Currently, the cause of RA is unknown and there is no satisfactory treatment for RA. Many therapeutic agents have been developed and utilized to reduce disease-related pain and inflammation, such as disease-modifying antirheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs), but they often produce intolerable side effects. To address this need and other needs, the present invention, in one embodiment, provides a method for treating RA using a reversible inhibitor of DPP1 of formula (I), (II), or (III). In one embodiment, there is provided a method for treating RA in a subject in need thereof, the method comprising administering to the subject, over a period of administration, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof. In a further embodiment, the method comprises reducing neutrophilic inflammation in the subject.

[0232] Inflammatory bowel disease (IBD) is a group of inflammatory conditions that affect the colon and small intestine. The most common forms of IBD are Crohn's disease and ulcerative colitis. In one embodiment, the present invention addresses the need for new IBD therapies. Specifically, in one embodiment, there is provided a method for treating inflammatory bowel disease (IBD) in a subject in need thereof. The method comprises administering to the subject, over a period of administration, a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.

[0233] In a further embodiment, the IBD is Crohn's disease or ulcerative colitis. In an even further embodiment, the method comprises reducing neutrophilic inflammation in a subject.

[0234] The length of the administration period in any given case can vary depending on the nature and severity of the condition being treated and / or prevented and can be determined by a physician. In one embodiment, the administration period begins at approximately the time of diagnosis of the condition / disease and continues throughout the patient's lifetime.

[0235] In some embodiments, the administration period is about 30 days, about 35 days, about 40 days, about 45 days, about 50 days, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 30 months, about 36 months, about 4 years, about 5 years, about 10 years, about 15 years, or about 20 years. In some embodiments, the compounds or compositions disclosed herein can be administered for about 24 weeks. In some embodiments, the compounds or compositions disclosed herein can be administered for about 52 weeks. In yet another embodiment, the administration period is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, or at least about 20 years.

[0236] In some embodiments, the administration period of the methods provided herein is at least about 30 days, at least about 35 days, at least about 40 days, at least about 45 days, at least about 50 days, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years. In another embodiment, the administration period for the methods provided herein is from about 30 days to about 180 days. In another embodiment, the administration period is from about 30 days to about 36 months, or from about 30 days to about 30 months, or from about 30 days to about 24 months, or from about 30 days to about 18 months, or from about 30 days to about 12 months, or from about 30 days to about 6 months, or from about 6 months to about 30 months, or from about 6 months to about 24 months, or from about 6 months to about 18 months, or from about 12 months to about 36 months, or from about 12 months to about 24 months.

[0237] In one embodiment, the administration period is from about 1 year to about 30 years. For example, in one embodiment, the administration period is from about 1 year to about 25 years, from 1 year to about 20 years, from about 1 year to about 15 years, from about 1 year to about 10 years, from about 1 year to about 5 years, from about 1 year to about 3 years, from about 1 year to about 2 years, from about 2 years to about 15 years, from about 2 years to about 10 years, from about 2 years to about 8 years, from about 2 years to about 5 years, from about 2 years to about 4 years, or from about 2 years to about 3 years.

[0238] In one embodiment of the method, during the administration period, the subject is administered the composition once a day. In another embodiment, during the administration period, the patient is administered the composition twice a day, or every other day, or once a week. In another embodiment, the administration is every other day, every three days, three times a week, or four times a week.

[0239] In one embodiment, the oral dosage form is administered once a day. In a further embodiment, the oral dosage form is administered at approximately the same time each day, for example, before breakfast. In another embodiment, the composition comprising an effective amount of formula (I), (II), or (III) is administered twice a day. In yet another embodiment, the composition comprising an effective amount of formula (I), (II), or (III) is administered once a week, every other day, every three days, twice a week, three times a week, four times a week, or five times a week.

[0240] In one embodiment, the administration is via the oral route. In a further embodiment, the composition is administered once a day.

[0241] The dosage administered varies depending on the compound of formula (I), (II), or (III) used, the method of administration, and the desired therapeutic result. For example, in one embodiment, the daily dosage of the compound of formula (I), (II), or (III) can be in the range of 0.05 micrograms per kilogram of body weight (μg / kg) to 100 micrograms per kilogram of body weight (μg / kg) when inhaled. Alternatively, in one embodiment, when the compound of formula (I), (II), or (III) is administered orally, the daily dosage of the compound of the present disclosure can be in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0242] The compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, may be used by itself, but the compound / salt (active ingredient) of formula (I), (II), or (III) is generally administered in the form of a pharmaceutical composition with pharmaceutically acceptable adjuvants, diluents, and / or carriers. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in “Pharmaceuticals - The Science of Dosage Form Designs”, M.E. Aulton, Churchill Livingstone, 2nd Ed. 2002.

[0243] Depending on the mode of administration, the pharmaceutical composition preferably contains from 0.05 to 99% by weight (weight percent), more preferably from 0.05 to 80% by weight, even more preferably from 0.10 to 70% by weight, and still even more preferably from 0.10 to 50% by weight of the active ingredient, with all weight percents being based on the total composition.

[0244] The present disclosure also provides a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as defined above, or a pharmaceutically acceptable salt thereof, in relation to a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0245] The present disclosure further provides a process for preparing a pharmaceutical composition of the present disclosure, which includes mixing a compound of formula (I), (II), or (III) as defined above, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0246] The pharmaceutical composition can be administered locally (e.g., to the skin, or to the lung and / or airways), for example, in the form of a cream, solution, suspension, heptafluoroalkane (HFA) aerosol, and dry powder formulation (e.g., a formulation within an inhalation device known as Turbuhaler®), or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules, or by parenteral administration in the form of a sterile solution, suspension, or emulsion for injection (including intravenous, subcutaneous, intramuscular, intra-arterial, or infusion), or by rectal administration in the form of suppositories.

[0247] For oral administration, the compounds of the present disclosure may be mixed with adjuvants, diluents, or carriers such as, for example, lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; disintegrants such as cellulose derivatives, and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. When coated tablets are required, the core prepared as described above may be coated with a suitable polymer dissolved or dispersed in water or an easily volatile organic solvent. Alternatively, the tablets may be coated with a concentrated sugar solution that may contain, for example, gum arabic, gelatin, talc, and titanium dioxide.

[0248] For the preparation of soft gelatin capsules, the compounds of the present disclosure may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using pharmaceutical excipients such as those for the tablets described above. Also, liquid or semi-solid formulations of the compounds of the present disclosure may be filled into hard gelatin capsules.

[0249] Liquid preparations for oral administration may be in the form of syrups, solutions, or suspensions. Solutions may contain, for example, the compounds of the present disclosure, and the remainder may contain a mixture of sugar, and ethanol, water, glycerol, and propylene glycol. Optionally, such liquid preparations may contain a coloring agent, a flavoring agent, saccharin, and / or a thickening agent such as carboxymethylcellulose. Further, other excipients known to those skilled in the art may be used when preparing formulations for oral use.

[0250] The numbered embodiments of the present disclosure Numbered embodiments - Set A In addition to the above disclosure, the following examples, and the appended claims, the present disclosure describes the following numbered embodiments. 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, [ka] , During the ceremony, R 1 but, [ka] and R 2 but, [ka] and X1, X2, and X3 are independently O, S, or NR 3 , or CR 3 R 4 and Each R 3 , R 4 , and R 5 are independently H, F, Cl, Br, I, or C1-C6 alkyl; Each R 6 are independently H or C1-C6 alkyl; Each Y is independently O, S, or CHR 6 , or NR 6 and m and m' are each independently an integer of 0 to 3, and the sum of m and m' is ≦3; each n, n', and n'' is independently an integer from 0 to 3, and the sum of n, n', and n'' is ≦4; L, [ka] and however, (i)R 1 but, [ka] and when X1 is -CH2-, L and R 2 Together, [Chemical formula] rather than, or (ii) R 1 is [Chemical formula] when it is, L and R 2 together form [Chemical formula] rather than (iii) R 1 is [Chemical formula] and when L is [Chemical formula] when it is, R 2 is [Chemical formula] rather than, or (iv) R 1 is [Chemical formula] and when L is [Chemical formula] when it is, R 2 is [Chemical formula] not, a compound, or a pharmaceutically acceptable salt thereof. 2. R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 3.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 4.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 5.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 6.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 7.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. 8.R 1 is [Chemical formula] The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 1 and m' is 1, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 1 and m' is 2, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 2 and m' is 1, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 1 and m' is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 0 and m' is 1, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 2 and m' is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 0 and m' is 2, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 8, wherein m is 0 and m' is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 16, wherein X1 is O, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 16, wherein X1 is S, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 16, wherein X1 is NH, or a pharmaceutically acceptable salt thereof. The compound according to any one of Embodiments 6 to 16, wherein X1 is CH2, or a pharmaceutically acceptable salt thereof. 21. R 1 is

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Examples

[0251] The present invention will be further illustrated by reference to the following examples. However, it should be noted that these examples are illustrative as in the above-described embodiments and should not be construed as limiting the scope of the present invention in any way.

[0252] The following abbreviations are used in the examples section and the figures referred to therein.

[0253] Boc: tert - butoxycarbonyl

[0254] Bu4NF: tetra - n - butylammonium fluoride

[0255] Bu3SNH: Tri-n-butyltin hydride

[0256] DCM: Dichloromethane

[0257] DIEA: N,N-Diisopropylethylamine

[0258] DIPEA: N,N-Diisopropylethylamine

[0259] DMF: Dimethylformamide

[0260] EdCl: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0261] Et: Ethyl

[0262] HCOOH: Formic acid

[0263] HOBT: Hydroxybenzotriazole

[0264] K3PO4: Potassium phosphate

[0265] LiHMDS: Lithium bis(trimethylsilyl)amide

[0266] mCPBA: meta-Chloroperbenzoic acid

[0267] Pd(dtbpf)Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0268] RT: Room temperature

[0269] TBDPS: tert-Butyldiphenylsilyl

[0270] TBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate

[0271] t-BuOK: Potassium tert-butoxide

[0272] THF: Tetrahydrofuran

[0273] Synthesis of Example 1 - IWD - 002 The synthetic route for IWD-002 ((1R,3S,5R)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide) is provided below and also shown in Figure 1.

Chemical formula

[0274] To a solution of compound A (600 mg, 1.61 mmol) and 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (487.83 mg, 1.77 mmol) in THF (24 mL), a solution of K3PO4 (684.36 mg, 3.22 mmol) in H2O (6 mL) was added at 20 °C, and then di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (63.04 mg, 96.72 μmol) was added to the solution at 20 °C under N2. The reaction mixture was stirred at 80 °C for 1 h. LC-MS indicated that compound A was completely consumed and a product with the desired mass was detected. The reaction mixture was quenched by adding water (40 mL) at 20 °C and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO (registered trademark), 4 g SepaFlash (registered trademark) Silica Flash Column, eluent with a gradient of 0 - 20% ethyl acetate / petroleum ether, 36 mL / min) to obtain compound B (600 mg, yield 94.60%) as a brown solid. 11H NMR: (400 MHz, DMSO-d6) δ ppm 7.86 (br d, J = 7.89 Hz, 1) 7.66 (d, J = 8.11 Hz, 2H) 7.58 (s, 1H) 7.33 - 7.45 (m, 4H) 4.69 (q, J = 8.04 Hz, 1H) 3.40 (s, 3H) 3.09 (br d, J = 7.67 Hz, 2H) 1.37 (s, 9H)

[0275] A solution of compound B (600 mg, 1.53 mmol) in formic acid (0.5 mL) was stirred at 50 °C for 0.25 h. LC-MS indicated that compound B was completely consumed and a product with the desired mass was detected. The reaction mixture was concentrated to obtain a residue, to which a saturated aqueous solution of NaHCO3 (30 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound C (400 mg, yield 89.42%) as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 7.65 (d, J = 8.11 Hz, 2H) 7.58 (d, J = 1.10 Hz, 1H) 7.36 - 7.46 (m, 4H) 3.95 - 4.04 (m, 1H) 3.40 (s, 3H) 2.88 - 3.03 (m, 2H) 2.42 (br s, 2H)

[0276] To a solution of Compound D (116.22 mg, 511.39 μmol) in DMF (3 mL), 3-(ethyliminomethylamino)-N,N-dimethyl-propan-1-amine, hydrochloride (147.05 mg, 767.08 μmol), 1-hydroxybenzotriazole (103.65 mg, 767.08 μmol), and DIEA (198.28 mg, 1.53 mmol, 267.22 μL) were added at 20 °C. After the addition, the mixture was stirred at 20 °C for 30 minutes, and then Compound C (150 mg, 511.39 μmol) in DMF (3 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. LC-MS indicated that Compound C was completely consumed and a product with the desired mass was detected. The reaction mixture was quenched by adding water (15 mL) at 20 °C and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®, 1 g SepaFlash® Silica Flash Column, eluent with a gradient of 0 - 40% ethyl acetate / petroleum ether, 36 mL / min) to obtain Compound E (225 mg, yield 87.55%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 8.68 (d, J = 8.55 Hz, 1H) 7.66 (d, J = 8.11 Hz, 2H) 7.57 (s, 1H) 7.36 - 7.45 (m, 4H) 4.94 - 5.12 (m, 1H) 3.68 - 3.91 (m, 1H) 3.40 (s, 3H) 3.17 (br d, J = 8.33 Hz, 2H) 2.11 - 2.19 (m, 1H) 1.49 (br dd, J = 3.40, 1.64 Hz, 3H) 1.32 (br s, 9H) 0.63 - 0.74 (m, 1H) 0.38 (td, J = 4.93, 2.41 Hz, 1H)

[0277] A solution of Compound E (100 mg, 198.98 umol) in formic acid (1 mL) was stirred at 20 °C for 16 h. LC-MS indicated that Compound E was completely consumed and a product with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give IWD-002 (14.5 mg, yield 16.12%) as a white solid. Column: Phenomenex Luna C18 75×30 mm×3 um, mobile phase: [water (FA)-ACN], B%: 10% - 50%, 8 min. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 8.58 (d, J = 8.63 Hz, 1H) 8.15 (s, 1H) 7.66 (d, J = 8.25 Hz, 2H) 7.58 (d, J = 1.13 Hz, 1H) 7.34 - 7.44 (m, 4H) 5.00 (q, J = 7.88 Hz, 1H) 3.40 (s, 3H) 3.31 (t, J = 8.63 Hz, 1H) 3.19 (d, J = 8.25 Hz, 2H) 2.75 (td, J = 5.91, 2.69 Hz, 1H) 2.03 (dd, J = 12.26, 8.25 Hz, 1H) 1.50 (ddd, J = 12.41, 8.91, 5.32 Hz, 1H) 1.22 - 1.33 (m, 1H) 0.29 - 0.41 (m, 2H)

[0278] Synthesis of Example 2 - (2S,3αR,6αS)-N-((S)-1-cyano-2-(4’-cyano-[1,1’-biphenyl]-4-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (IWD - 004) The synthetic route for IWD-004 ((2S,3αR,6αS)-N-((S)-1-cyano-2-(4’-cyano-[1,1’-biphenyl]-4-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide) is provided below and summarized in Figure 2. IWD-004 is also shown below.

Chemical Structure

[0279] To a solution of Compound 0 (350 mg, 896.94 μmol) in CH2Cl2 (10.5 mL) was added a solution of methoxycarbonyl-(triethylammonio)sulfonyl-azanide (470.24 mg, 1.97 mmol) in CH2Cl2 (1 mL) at 0 °C. The mixture was stirred at 20 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in 0% - 16% petroleum ether to give Compound A (430 mg, 82.04% yield) as a white solid. 1 1H NMR: (400 MHz, DMSO-d6) δ = 7.79 (br d, J = 8.03 Hz, 1H) 7.68 (d, J = 8.16 Hz, 2H) 7.12 (d, J = 8.28 Hz, 2H) 4.64 (q, J = 7.86 Hz, 1H) 2.92 - 3.07 (m, 2H) 1.35 (s, 9H)

[0280] To a solution of Compound A (300 mg, 806.02 μmol) and (4-cyanophenyl)boronic acid (142.12 mg, 967.22 μmol) in THF (12 mL) was added K3PO4 (342.18 mg, 1.61 mmol) in water (3 mL) at 20 °C. The mixture was degassed and purged with N2 three times, then di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (31.52 mg, 48.4 μmol) was added under an N2 atmosphere. The mixture was stirred at 80 °C for 1 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched by adding water (20 mL) at 0 °C and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in 0% - 16% petroleum ether to give Compound F (430 mg, 82.04% yield) as a white solid. 11H NMR: (400 MHz, DMSO-d6) δ = 7.86 - 7.95 (m, 4H) 7.84 (br d, J = 8.13 Hz, 1H) 7.73 (m, J = 8.25 Hz, 2H) 7.45 (m, J = 8.13 Hz, 2H) 4.71 (q, J = 7.71 Hz, 1H) 3.32 (s, 1H) 3.05 - 3.18 (m, 2H) 1.36 (s, 9H) 0.84 (br d, J = 6.88 Hz, 1H).

[0281] A solution of compound F (80 mg, 230.28 μmol) in HCOOH (0.8 mL) was stirred at 50 °C for 0.25 h. LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The residue was adjusted to pH = 8 with aqueous NaHCO3 and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound G (112 mg, yield 87.41%) as a yellow solid. 1 1H NMR: (400 MHz, DMSO-d6) δ = 7.87 - 7.94 (m, 4H) 7.71 - 7.75 (m, 2H) 7.42 - 7.47 (m, 2H) 3.96 - 4.05 (m, 1H) 3.34 (s, 1H) 3.08 - 3.26 (m, 1H) 2.83 - 3.07 (m, 2H)

[0282] To a solution of Compound G (88.43 mg, 343.72 μmol) in DMF (1.8 mL) were added DIEA (133.27 mg, 1.03 mmol, 179.61 μL), EDCI (98.84 mg, 515.58 μmol), and HOBt (69.67 mg, 515.58 μmol) at 20 °C, and then a solution of 4-[4-[(2S)-2-amino-2-cyano-ethyl]phenyl]benzonitrile (85 mg, 343.72 μmol) in DMF (0.2 mL) was added at 0 °C. The reaction mixture was stirred at 20 °C for 16 h. LCMS indicated that the reaction was complete. The reaction mixture was quenched by adding water (5 mL) at 0 °C and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate = 1:4) to give Compound I (110 mg, yield 59.79%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ = 1.22 (s, 5H) 1.21 - 1.27 (m, 1H) 1.37 (s, 3H) 1.77 - 1.95 (m, 2H) 2.72 - 2.90 (m, 1H) 3.11 - 3.23 (m, 2H) 3.43 - 3.50 (m, 2H) 3.52 - 3.59 (m, 1H) 3.73 (br d, J = 9.43 Hz, 1H) 4.14 (dd, J = 8.44, 2.52 Hz, 1H) 4.22 - 4.32 (m, 1H) 4.33 - 4.40 (m, 1H) 4.99 (d, J = 7.67 Hz, 1H) 7.42 - 7.49 (m, 2H) 7.73 (d, J = 8.11 Hz, 2H) 7.84 - 7.95 (m, 4H)

[0283] A solution of Compound I (100 mg, 205.52 μmol) in HCOOH (1 mL) was stirred at 20 °C for 16 h. LCMS indicated that the reaction was complete. The reaction product was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions) to give IWD-004 (15 mg, yield 18.19%, purity 96.3%) as a white solid. Column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (FA)-ACN], B%: 20% - 60%, 8 min.1 1H NMR: (400 MHz, methanol-d4) δ = 8.36 (br s, 1H) 7.81 (s, 4H) 7.69 (d, J = 8.11 Hz, 2H) 7.45 (d, J = 8.11 Hz, 2H) 5.11 (t, J = 7.67 Hz, 1H) 4.90 (s, 5H) 4.20 (t, J = 6.14 Hz, 1H) 3.87 - 3.98 (m, 2H) 3.67 - 3.77 (m, 2H) 3.63 (dd, J = 10.52, 5.26 Hz, 1H) 3.17 - 3.30 (m, 2H) 2.93 - 3.02 (m, 1H) 2.07 - 2.15 (m, 1H) 1.99 - 2.07 (m, 1H)

[0284] Synthesis of Example 3 - (2S,3αR,6αS)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (IWD - 005) (2S,3αR,6αS)-N-((S)-1-Cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (IWD-005) is considered below and also provided in Figure 3 for the synthetic route carried out on it.

Chemical formula

[0285] To a mixture of NaIO4 (0.65 M, 40.00 mL) and SiO2 (9.09 g, 151.33 mmol) in DCM (80 mL), compound J (4 g, 30.27 mmol) was added all at once under N2 at 0 °C. The mixture was stirred at 20 °C for 2 hours. TLC indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was extracted with CH2Cl2 (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain compound K (2.5 g, yield 82.50%) as a colorless oil. 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 4.03 (dt, J = 5.47, 1.39 Hz, 2H), 4.16 (s, 2H), 5.15 - 5.21 (m, 1H), 5.28 (dd, J = 17.26, 1.75 Hz, 1H), 5.82 - 5.98 (m, 1H), 9.59 (s, 1H).

[0286] To a mixture of (5S)-5-phenylmorpholin-2-one (1 g, 5.64 mmol) and Compound K (847.48 mg, 8.47 mmol) in toluene (20 mL) under N2 at 25 °C. The mixture was stirred at 110 °C for 16 h. LCMS indicated that the starting materials were completely consumed. The reaction mixture was concentrated in vacuo to afford the product. The crude product was purified by silica gel chromatography (eluting with petroleum ether / ethyl acetate = 2:1) to give Compound L (1.1 g, yield 75.17%) as a pale yellow solid. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 1.85 (d, J = 6.13 Hz, 1H), 2.44 - 2.50 (m, 1H), 2.72 - 2.84 (m, 1H), 3.13 - 3.21 (m, 1H), 3.24 - 3.31 (m, 1H), 3.39 - 3.52 (m, 2H), 3.59 (dd, J = 8.82, 3.19 Hz, 1H), 3.96 - 4.03 (m, 1H), 4.25 (s, 1H), 4.27 (d, J = 1.38 Hz, 1H), 4.32 (dd, J = 7.38, 4.00 Hz, 1H), 7.27 - 7.34 (m, 1H), 7.38 (t, J = 7.38 Hz, 2H), 7.43 - 7.50 (m, 2H).

[0287] To a mixture of Pd(OH)2 (300 mg, 427.23 μmol) and TFA (527.67 mg, 4.63 mmol) in ethyl acetate (10 mL), Compound L (600 mg, 2.31 mmol) was added under H2 (15 psi) at 25 °C. The mixture was stirred at 25 °C for 12 h. LCMS indicated that the starting materials were completely consumed. The reaction mixture was filtered and the filtrate was concentrated to give Compound M (350 mg, yield 96.24%) as a white solid. 1 H NMR: (400 MHz, DMSO-d6) δ ppm 2.14 - 2.23 (m, 2H), 2.98 - 3.09 (m, 1H), 3.57 - 3.66 (m, 2H), 3.78 (dd, J = 9.26, 2.50 Hz, 1H), 4.04 (br d, J = 10.88 Hz, 1H), 4.26 (t, J = 8.57 Hz, 1H), 4.33 (br t, J = 6.13 Hz, 1H), 9.23 - 9.95 (m, 1H).

[0288] A solution of compound M (150 mg, 954.40 μmol) in dioxane (2 mL) was added with a solution of Na2CO3 (202.31 mg, 1.91 mmol) in water (4 mL) at 20 °C. A solution of (Boc)2O (312.44 mg, 1.43 mmol, 328.89 μL) in dioxane (2 mL) was added to the reaction mixture, and the mixture was stirred at 20 °C for 16 h. LC-MS indicated that compound M was consumed and a product with the desired mass was detected. The reaction mixture was quenched by adding water (10 mL) at 20 °C and then extracted with ethyl acetate (5 mL × 3). The aqueous layer was adjusted to pH 4 with 1N HCl. Then, the mixture was extracted with ethyl acetate (10 mL × 6), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound N (100 mg, yield 40.72%) as a colorless oil. 1 1H NMR: (400 MHz, DMSO-d6) δ ppm 12.02 (br s, 1H) 4.20 - 4.36 (m, 2H) 3.78 (br d, J = 9.29 Hz, 1H) 3.47 - 3.66 (m, 3H) 2.89 (br s, 1H) 1.92 - 2.20 (m, 2H) 1.39 (br s, 9H).

[0289] To a solution of Compound N (96.49 mg, 375.02 μmol) in DMF (2 mL), 3-(ethyliminomethylamino)-N,N-dimethyl-propan-1-amine, hydrochloride (107.84 mg, 562.53 μmol), 1-hydroxybenzotriazole (76.01 mg, 562.53 μmol), and DIEA (145.40 mg, 1.13 mmol, 195.96 μL) were added at 20 °C. After the addition, the mixture was stirred at this temperature for 30 minutes, and then Compound I (110 mg, 375.02 μmol) in DMF (2 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. LC-MS indicated that Compound I was completely consumed and a product with the desired mass was detected. The reaction mixture was quenched by adding water (15 mL) at 20 °C and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (ISCO®, 1 g SepaFlash® Silica Flash Column, eluent with a 0 - 60% ethyl acetate / petroleum ether gradient, 36 mL / min) to give Compound O (162 mg, yield 81.11%) as a white solid. 1 H NMR: (400 MHz, chloroform-d) δ ppm 7.51 - 7.61 (m, 2H) 7.34 - 7.45 (m, 3H) 7.27 - 7.33 (m, 2H) 7.13 (d, J = 1.32 Hz, 1H) 5.02 - 5.20 (m, 1H) 4.45 (d, J = 7.89 Hz, 1H) 4.16 - 4.23 (m, 1H) 3.90 (dd, J = 9.98, 2.74 Hz, 1H) 3.76 (d, J = 9.21 Hz, 1H) 3.69 (dt, J = 9.92, 6.55 Hz, 1H) 3.57 (dd, J = 9.32, 4.93 Hz, 1H) 3.46 (s, 3H) 3.02 - 3.20 (m, 3H) 2.46 (dd, J = 12.72, 8.33 Hz, 1H) 1.79 - 1.89 (m, 1H) 1.37 - 1.53 (m, 9H).

[0290] A solution of Compound O (150 mg, 281.64 μmol) in formic acid (1.5 mL) was stirred at 20 °C for 16 h. LC-MS indicated that Compound O was completely consumed and a product with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA conditions) to give IWD-005 (33.3 mg, yield 24.29%) as a white solid. Column: Phenomenex Luna C18 75×30 mm×3 μm, mobile phase: [water (FA)-ACN], B%: 20% - 60%, 8 min. 1 1H NMR: (400 MHz, chloroform-d) δ ppm 8.07 (br s, 1H) 7.82 (br d, J = 8.77 Hz, 1H) 7.56 (d, J = 8.11 Hz, 2H) 7.37 (d, J = 8.11 Hz, 2H) 7.29 - 7.34 (m, 1H) 7.27 - 7.29 (m, 1H) 7.14 (d, J = 1.53 Hz, 1H) 5.09 - 5.20 (m, 1H) 3.99 (t, J = 7.34 Hz, 1H) 3.76 - 3.84 (m, 2H) 3.66 - 3.75 (m, 2H) 3.63 (dd, J = 10.19, 4.71 Hz, 1H) 3.47 (s, 3H) 3.16 (d, J = 7.02 Hz, 2H) 2.77 (qt, J = 7.42, 3.56 Hz, 1H) 2.13 (dt, J = 12.93, 7.67 Hz, 1H) 1.97 - 2.06 (m, 1H).

[0291] Synthesis of Example 4 - (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)propanenitrile hydrochloride A synthetic scheme for (S)-2-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile hydrochloride (also referred to herein as BB01), which can be used as a reactant for obtaining a compound of formula (IA) and / or (II), is provided in Figure 4.

Chemical formula

[0292] Synthesis of Example 5 - Synthesis of Exemplary Cyclic Crosslinked α-Amino Derivatives which can be used as a reactant for obtaining the compound of formula (II)

Chem.

[0293] Synthesis of Example 6 - Synthesis of Exemplary Cyclic Sulfonyl α-Amino Moieties which can be used as a reactant for obtaining the compound of formula (II)

Chem.

[0294] Synthesis of Example 7 - Exemplary Exo-βNH 2 For an exemplary exo-betaine NH2 cyclic moiety that can be used as a reactant for obtaining the compound of the present invention

Chem.

[0295] Cyclic Derivative Moiety which can be used as a reactant for obtaining the compound of the present invention

Chem.

[0296] Synthesis of Example 8 - Synthesis of Exemplary β-Aminospiro Ring Moieties A synthetic scheme for B1-26 ((S)-3-amino-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-3-methylbutanamide), an exemplary DPP1 inhibitor having a beta-carbon substituted moiety, is provided in FIG. 10. [Chemistry] B1-26

[0297] The deprotection conditions of B1-26-2 referred to in Figure 10 are provided in Table 12 below. [Table 13]

[0298] Synthesis of Example 9 - B1 - 26 ((S)-3-amino-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)-3-methylbutanamide) The synthetic scheme of B1-26 ((S)-3-amino-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-3-methylbutanamide) (shown below) is provided in Figure 11. [Chemistry] B1-18 (diastereomer mixture 1:1)

[0299] Synthesis of Example 10 - B1 - 18 (N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)-2-(morpholin-3-yl)acetamide) Example 11 - IC50 Assay The test substance was applied to active mouse DPP1 enzyme (R&D Systems, Minneapolis MN) in assay buffer (50 mM MES pH 5.5, 50 mM NaCl, 5 mM DTT) at a total reaction volume of 125 μL. A 5% DMSO addition to 25 μL of the compound in assay buffer was first added to 50 μL of active mouse DPP1 enzyme at a concentration of 62.5 pg / μL, pre-incubated at 37 °C for 10 minutes, and then 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem, St. Torrance, CA) was added to obtain a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage was measured at 37 °C for 90 minutes, and fluorescence at excitation / emission 350 / 450 nm was measured every 5 minutes. The DPP1 concentration was interpolated based on its activity against a standard curve of recombinant active mouse DPP1 enzyme. The IC50 value for each compound was calculated using the four-parameter fit equation y = (A + ((B - A) / (1 + ((C / x)^D)))), which appears as XLFit's equation 205 (four-parameter logistic model or sigmoid dose-response model) via the XLFit add-in for Microsoft Excel (IDBS version 5.3.1.3). Default constraints were used for each parameter. The IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited when compared to the control without compound.

[0300] The results are provided in Figures 12 and 13, and Table 13 below.

Table 14

[0301] Mouse DPP1 Enzyme IC50 Assay Recombinant human DPP1 enzyme (R&D Systems, Minneapolis, MN) was first proteolytically processed to its mature form using recombinant human cathepsin L (R&D Systems) in a buffer consisting of 20 mM citric acid pH 4.5, 150 mM NaCl, 1 mM EDTA, and 10 mM DTT. Test substances were applied to the activated human DPP1 enzyme in assay buffer (25 mM MES pH 6.0, 50 mM NaCl, 5 mM DTT) at a total reaction volume of 125 μL. A 5% DMSO addition to 25 μL of the compound in assay buffer was first added to 50 μL of the activated human DPP1 enzyme at a concentration of 1 ng / μL and pre-incubated at 37 °C for 10 minutes, after which 50 μL of 1000 μM H-Gly-Arg-AMC substrate (Bachem, St. Torrance, CA) was added to obtain a final substrate concentration of 400 μM and a final DMSO concentration of 1%. Substrate cleavage was measured at 37 °C for 90 minutes, and fluorescence at excitation / emission 350 / 450 nm was measured every 5 minutes. The DPP1 concentration was interpolated based on its activity against a standard curve of the activated human recombinant DPP1 enzyme. The IC50 value for each compound was calculated using the four-parameter fitting equation y = {A + [(B - A)] / [1 + ((C / x)^D)]}, which appears as XLFit's equation 205 (four-parameter logistic model or sigmoid dose-response model) via the XLFit add-in for Microsoft Excel (IDBS version 5.3.1.3). Default constraints were used for each parameter. The IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited when compared to a control without compound.

[0302] The results are provided in Figures 14 and 15, and Table 14 below.

Table 15

[0303] Human DPP1 Enzyme IC50 Assay HL-60 cells (ATCC, Manassas, VA) were maintained in RPMI-1640 supplemented with 20% heat-inactivated FBS and 1X antibiotic-antimycotic (Cytiva, Marlborough, MA). The medium was changed every 3 - 4 days to keep the cell density below 1×10 6 cells per mL. Before the assay, cells were collected by centrifugation at 500 rcf for 3 minutes, resuspended in PBS, and counted. The cells were diluted with PBS to a concentration of 5×10 5 viable cells / mL and transferred to a black 96-well plate at 60 μL / well for the assay. The test substances were diluted in PBS + 0.5% DMSO and 20 μL was added to each assay well. The compounds were pre-incubated with the cells in a cell culture incubator maintained at 5% CO2, gently shaken at 100 rpm for 60 minutes at 37 °C, and then 20 μL of 500 μM H-Gly-Phe-AFC substrate (MP Biomedicals, Solon, OH) was added to each well. After returning the plate to the incubator and shaking at 100 rpm for 30 minutes, fluorescence was measured at an excitation / emission of 400 / 505 nm. The percentage of inhibition was calculated from the RFU values compared to the control cell wells with only PBS + 0.5% DMSO added. The IC50 value of each compound was calculated using the four-parameter fitting equation y=(A+((B - A) / (1+((C / x)^D)))) as it appears in XLFit's equation 205 (four-parameter logistic model or sigmoid dose-response model) via the XLFit add-in for Microsoft Excel (IDBS version 5.3.1.3). The IC50 was defined as the compound concentration at which 50% of the enzyme activity was inhibited when compared to the control without the compound.

[0304] The results of these assays are provided in Figures 16 and 17, and Table 15 below.

Table 16

[0305] DPP1 Cell IC50 Assay The mouse and human assays described in Example 11 were performed on the compounds listed in Table 16.

Table 17-1

Table 17-2

Table 17-3

Table 17-4

Table 17-5

Table 17-6

Table 17-7

Table 17-8

Table 17-9

Table 17-10

Table 17-11

Table 17-12

[0306] Example 12 - IC50 Assay Example 13. Compound 145: (S)-N-((S)-1-cyano-2-(4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide Synthesis

Chemical formula

Chemical formula

[0307] To a stirred solution of 5-bromo-3-(methyl-d3)benz[d]oxazol-2(3H)-one (14 g, 60.59 mmol, 1.0 equiv) and bis(pinacolato)diboron (18.5 g, 72.70 mmol, 1.2 equiv) in dioxane (150 mL), AcOK (11.89 g, 121.18 mmol, 2.0 equiv), Xphos (17.3 g, 36.35 mmol, 0.6 equiv) and Pd(OAc)2 (2.7 g, 12.11 mmol, 0.2 equiv) were added in sequence. The resulting mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 (2 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (12:1) to afford 3-(methyl-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benz[d]oxazol-2(3H)-one (13 g, 77.1%) as a brown solid.

[0308] LCMS(ES,m / z):[M+H] + : 279. Synthesis of tert-butyl N-[(1S)-1-carbamoyl-2-(4-iodophenyl)ethyl]carbamate

Chemical formula

[0309] (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-iodophenyl)propanoic acid (140 g, 357.86 mmol, 1.0 equiv) and NH4Cl (38.3 g, 715.73 mmol, 2.0 equiv) in DMF (1.4 L) were added portionwise with DIEA (138.8 g, 1073.60 mmol, 3.0 equiv) and HATU (163.3 g, 429.44 mmol, 1.2 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The resulting mixture was diluted with water (5 L). The precipitated solid was collected by filtration, washed with water (1 L × 2), and dried under an infrared lamp for 4 h. Thus, tert-butyl N-[(1S)-1-carbamoyl-2-(4-iodophenyl)ethyl]carbamate (130 g, 93.0%) was obtained as a white solid. LCMS (ES, m / z): [M+H] + : 391. Synthesis of tert-butyl N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamate [Chemical formula]

[0310] TFAA (139.94 g, 666.29 mmol, 2.0 equiv) was added dropwise to a stirred solution of tert-butyl N-[(1S)-1-carbamoyl-2-(4-iodophenyl)ethyl]carbamate (130 g, 333.14 mmol, 1.0 equiv) and TEA (134.85 g, 1332.58 mmol, 4.0 equiv) in DCM (2 L) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with water (1.5 L) and extracted with CH2Cl2 (1 L × 3). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE:EA = 20:1 (300 mL). Thus, tert-butyl N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamate (115 g, 92.7%) was obtained as a white solid. LCMS (ES, m / z): [M+H] + : 373. Synthesis of tert-butyl N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamate

Chem.

[0311] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]carbamate (1.5 g, 4.03 mmol, 1.0 equiv) and 3-(2H3)methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (1.35 g, 4.83 mmol, 1.2 equiv) in dioxane (20 mL) and H2O (2 mL) were added K2CO3 (1.11 g, 8.06 mmol, 2.0 equiv) and Pd(dppf)Cl2 (0.29 g, 0.40 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (3:1) to give tert-butyl N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamate (1.3 g, 81.3%) as a brown solid. LCMS (ES, m / z): [M+H] + : 397。 (2S)-2-Amino-3-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}propanenitrile synthesis

Chem.

[0312] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamate (1.3 g, 3.27 mmol, 1.0 equiv) in ACN (13 mL) was added TsOH (1.69 g, 9.83 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The residue was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to afford (2S)-2-amino-3-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}propanenitrile (0.75 g, 77.1%) as a white solid. LCMS (ES, m / z): [M+H] + : 297. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

Chemical Structure

[0313] A stirred solution of (2S)-2-amino-3-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}propanenitrile (90 mg, 0.30 mmol, 1.2 equiv) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (51 mg, 0.21 mmol, 0.69 equiv) in DCM (2 mL) was treated with DIEA (98 mg, 0.75 mmol, 2.50 equiv) and HATU (115 mg, 0.30 mmol, 1.00 equiv) in several portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to afford (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (120 mg, 90.5%) as a white solid. LCMS (ES, m / z): [M+H] + : 524. Synthesis of (2S)-N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide [Chemical Structure]

[0314] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (110 mg, 0.21 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (98 mg, 0.57 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19×150 mm 5um; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% phase B, to 40% in 7 min); detector, UV 254 nm. The target fraction was lyophilized to give (2S)-N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-1,4-oxazepane-2-carboxamide (30 mg, 37.0%) as an off-white solid.

[0315] LCMS(ES,m / z):[M+H] + :424

[0316] 1 1H NMR(300MHz,DMSO-d6) δ 8.61(d,J=8.5Hz,1H),7.66(d,J=8.1Hz,2H),7.57(s,1H),7.44-7.35(m,4H),5.03(q,J=8.2Hz,1H),4.01(dd,J=8.0,3.6Hz,1H),3.90-3.80(m,1H),3.77-3.68(m,1H),3.24-3.18(m,2H),3.05(dd,J=14.3,3.7Hz,1H),2.83-2.73(m,1H),2.69-2.53(m,2H),1.76-1.69(m,2H).

[0317] Example 15. Synthesis of Compound 146: (S)-N-((S)-1-Cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

Chemical Structure

Chem.

Chem.

[0318] To a stirred solution of (2S,5R)-2-(4-bromo-2-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (37 g, 99.66 mmol, 1.0 eq) in ACN (330 mL), HCl (1N) (150 mL, 150.00 mmol, 1.5 eq) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 12 h. It was concentrated to remove the solvent, and the residue was acidified to pH 8 with saturated NaHCO3 (aqueous solution) and extracted with dichloromethane (300 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, methyl (2S)-2-amino-3-(4-bromo-2-fluorophenyl)propanoate (23 g, 83%) was obtained as a pale yellow oil and used in the next step without further purification. LCMS (ES, m / z): [M+H] + : 276. Synthesis of methyl (2S)-3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate

Chemical Structure

[0319] To a stirred mixture of methyl (2S)-2-amino-3-(4-bromo-2-fluorophenyl)propanoate (23.0 g, 83.30 mmol, 1.0 eq) and TEA (23.16 mL, 166.60 mmol, 2.0 eq) in DCM (350 mL), Boc2O (21.8 g, 99.96 mmol, 1.2 eq) was added at room temperature. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was washed with brine (200 mL × 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to give methyl (2S)-3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (22 g, 70%) as a pale yellow oil. LCMS (ES, m / z): [M+H] + : 376. (2S)-3-(4-Bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid synthesis

Chem.

[0320] To a stirred solution of methyl (2S)-3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoate (22.0 g, 58.47 mmol, 1.0 equiv) in MeOH (250 mL), NaOH (4.7 g, 116.95 mmol, 2.0 equiv) in H2O (150 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to remove the solvent, and the residue was acidified to pH 5 with citric acid and extracted with ethyl acetate (200 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, (2S)-3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (20 g, 94%) was obtained as a pale yellow oil. LCMS(ES, m / z): [M+H] + : 362. Synthesis of tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-carbamoylethyl]carbamate

Chem.

[0321] To a stirred mixture of (2S)-3-(4-bromo-2-fluorophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (20 g, 55.22 mmol, 1.0 equiv), NH4Cl (5.91 g, 110.44 mmol, 2 equiv), and DIEA (21.4 g, 165.66 mmol, 3 equiv) in DMF (200 mL) was added HATU (25.2 g, 66.26 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched with water (300 mL) at 0 °C and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to give tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-carbamoylethyl]carbamate (19 g, 95%) as a pale yellow oil. LCMS (ES, m / z): [M+H] + : 361. Synthesis of tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl]carbamate

Chemical Structure

[0322] To a stirred mixture of tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-carbamoylethyl]carbamate (10 g, 27.69 mmol, 1.0 equiv) and TEA (11.2 g, 110.74 mmol, 4.0 equiv) in DCM (100 mL) was added TFAA (8.7 g, 41.53 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was washed with brine (100 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (3:1) to give tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl]carbamate (7.5 g, 79%) as a pale yellow oil. LCMS (ES, m / z): [M+H] + : 343. Synthesis of (S)-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamic acid tert-butyl

Chemical Structure

[0323] A stirred mixture of tert-butyl N-[(1S)-2-(4-bromo-2-fluorophenyl)-1-cyanoethyl]carbamate (1.0 g, 2.91 mmol, 1.0 equiv), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (0.88 g, 3.20 mmol, 1.1 equiv) in dioxane (10 mL) and H2O (1 mL) was added with K2CO3 (0.8 g, 5.82 mmol, 2.0 equiv) and Pd(dppf)Cl2 (0.2 g, 0.29 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column chromatography eluting with PE / THF (4:1) to give tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1.1 g, 91%) as a yellow oil. LCMS (ES, m / z): [M+H] + : 412. Synthesis of (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile [Chemical formula]

[0324] To a 100 mL round-bottom flask, tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1.0 g, 2.43 mmol, 1.0 equiv), acetonitrile (30 mL) and TsOH (1.3 g, 7.29 mmol, 3.0 equiv) were added in sequence at room temperature. The resulting mixture was stirred at room temperature for 2 h. The pH value of the mixture was basified to 8 with saturated NaHCO3 (aqueous solution), and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (1.0 g, crude product) was obtained as a white solid and used in the next step without further purification. LCMS (ES, m / z): [M+H] + : 312. Synthesis of tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate [Chemical formula]

[0325] A stirred solution of (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (50 mg, 0.20 mmol, 1.0 equiv), (S)-2-amino-3-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (76 mg, 0.24 mmol, 1.2 equiv) and DIEA (79 mg, 0.61 mmol, 3.0 equiv) in DCM (5 mL) was treated with HATU (93 mg, 0.24 mmol, 1.2 equiv) portionwise at 0 °C in several times. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to afford (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl (70 mg, 64%) as a white solid. LCMS (ES, m / z): [M+H] + : 539. Synthesis of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

Chemical Structure

[0326] To an 8 mL vial were sequentially added tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (70 mg, 0.13 mmol, 1.0 equiv), ACN (3 mL), and TsOH (67 mg, 0.39 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was filtered, and the filtrate was purified by reverse-phase flash chromatography under the following conditions: C18-120 g column, mobile phase, MeCN / H2O (0.1% NH3·H2O), gradient from 10% to 80% in 10 min, detector, UV 254 nm. The target fraction was lyophilized to give (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (22.6 mg, 40%) as a white solid.

[0327] Analysis data LCMS(ES,m / z):[M+H] + :439.1

[0328] 1 H NMR(400MHz,DMSO-d6) δ 8.70(d,J=8.4Hz,1H),7.66(d,J=2.0Hz,1H),7.63-7.52(m,2H),7.52-7.42(m,2H),7.41(d,J=8.4Hz,1H),5.06(q,J=8.4Hz,1H),4.01(dd,J=8.0,3.6Hz,1H),3.90-3.84(m,1H),3.77-3.70(m,1H),3.41(s,3H),3.31-3.17(m,1H),3.06(dd,J=14.2,3.7Hz,1H),2.83-2.73(m,1H),2.68-2.54(m,2H),1.83-1.64(m,2H).

[0329] Example 16. Synthesis of Compound 147: (2S)-N-[(1S)-1-Cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]-1,4-oxazepane-2-carboxamide

Chemical formula

Chem.

Chem.

[0330] To a stirred solution of tert-butyl N-[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]carbamate (1.0 g, 2.74 mmol, 1.0 equiv) in ACN (12 mL) was added TsOH (1.41 g, 8.21 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The mixture was basified to pH 8 with saturated NaHCO3 (aqueous solution) and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to give 4'-[(2S)-2-amino-2-cyanoethyl]-3'-fluoro-[1,1'-biphenyl]-4-carbonitrile (600 mg, 82%) as a white solid. LCMS (ES) [M+1] + m / z: 266. Synthesis of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate

Chemical Structure

[0331] To a stirred solution of 4’-[(2S)-2-amino-2-cyanoethyl]-3’-fluoro-[1,1’-biphenyl]-4-carbonitrile (64 mg, 0.25 mmol, 1.2 eq) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (50 mg, 0.20 mmol, 1.0 eq) in DCM (2 mL) was added DIEA (79 mg, 0.61 mmol, 3.0 eq). To the above mixture was added HATU (93 mg, 0.25 mmol, 1.2 eq) portionwise at 0 °C in several times. The resulting mixture was stirred at 0 °C for an additional 1 h. The resulting mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to give (2S)-2-{[(1S)-1-cyano-2-{4’-cyano-3-fluoro-[1,1’-biphenyl]-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylic acid tert-butyl (90 mg, 89%) as an off-white solid. LCMS (ES) [M+1] + m / z: 493. Synthesis of (2S)-N-[(1S)-1-cyano-2-{4’-cyano-3-fluoro-[1,1’-biphenyl]-4-yl}ethyl]-1,4-oxazepane-2-carboxamide

Chemical Structure

[0332] To a stirred solution of tert-butyl (2S)-2-{[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}-1,4-oxazepane-4-carboxylate (90 mg, 0.18 mmol, 1.0 eq) in ACN (2 mL) was added TsOH (94 mg, 0.55 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19×150 mm, 5 μm, mobile phase, water (10 mmol / L NH3.H2O) and ACN (30% phase B, to 40% in 7 min), detector, UV, 220 nm. The target fraction was lyophilized to give (2S)-N-[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]-1,4-oxazepane-2-carboxamide (30 mg, 42%) as a white solid.

[0333] 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 8.6 Hz, 1H), 7.94 (s, 4H), 7.72 - 7.57 (m, 2H), 7.51 (t, J = 7.9 Hz, 1H), 5.14 - 5.00 (m, 1H), 4.00 (dd, J = 7.9, 3.6 Hz, 1H), 3.93 - 3.80 (m, 1H), 3.77 - 3.69 (m, 1H), 3.32 - 3.16 (m, 2H), 3.04 (dd, J = 14.2, 3.7 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.68 - 2.51 (m, 2H), 1.84 - 1.65 (m, 2H). LCMS (ES) [M+1] + m / z: 393

[0334] Example 17. Synthesis of Compound 148: (S)-N-((S)-1-Cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

Chem.

Chem.

Chemical formula

[0335] To a stirred solution of tert-butyl (S)-(1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamate (1 g, 2.41 mmol, 1.0 equiv) in ACN (10 mL) was added TsOH (1.25 g, 7.23 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The residue was basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to give (S)-2-amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (0.65 g, 85.7%) as an off-white solid. LCMS (ES) [M+1] + m / z: 315. Synthesis of tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate

Chemical Structure

[0336] To a stirred solution of (S)-2-amino-3-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (100 mg, 0.31 mmol, 1.2 eq) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (65 mg, 0.26 mmol, 1.0 eq) in DCM (1 mL), DIEA (102 mg, 0.79 mmol, 3.0 eq) and HATU (120 mg, 0.31 mmol, 1.2 eq) were added in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. The residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to give (S)-tert-butyl 2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 83.5%) as a white solid. LCMS (ES) [[M+1]] + m / z: 542. Synthesis of (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

Chemical Structure

[0337] To a stirred solution of tert-butyl (S)-2-(((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)carbamoyl)-1,4-oxazepane-4-carboxylate (120 mg, 0.22 mmol, 1.0 eq) in ACN (2 mL) was added TsOH (114 mg, 0.66 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% phase B, 40% in 7 min); detector, UV254 nm, to give (S)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (60 mg, 61%) as a white solid.

[0338] 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.61 - 7.54 (m, 2H), 7.52 - 7.36 (m, 3H), 5.06 (q, J = 8.2 Hz, 1H), 4.00 (dd, J = 7.8, 3.6 Hz, 1H), 3.91 - 3.83 (m, 1H), 3.80 - 3.66 (m, 1H), 3.29 - 3.13 (m, 2H), 3.05 (dd, J = 14.2, 3.6 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.66 - 2.56 (m, 2H), 1.83 - 1.65 (m, 2H).

[0339] LCMS (ES) [M+1]+ m / z: 442.

[0340] Example 18. Synthesis of Compound 149: (S)-N-(1-Cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Chemical Structure

Chem.

Chem.

[0341] To an 8 mL vial were sequentially added tert-butyl 3-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}azetidine-1-carboxylate (100 mg, 0.21 mmol, 1.0 equiv), ACN (3 mL), and TsOH (108 mg, 0.63 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g, mobile phase, MeCN / H2O (0.1% TFA), 10% - 50% gradient in 10 minutes; detector, UV 254 nm. Thereby, (S)-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (24.7 mg, 24%) was obtained as a white solid.

[0342] Analysis data LCMS(ES,m / z):[M-TFA+H] + :377

[0343] 1 H NMR(400MHz,DMSO-d6) δ 9.10-9.00(m,1H),8.65(brs,2H),7.69(d,J=8.1Hz,2H),7.58(d,J=1.6Hz,1H),7.47-7.37(m,4H),5.05(q,J=7.5Hz,1H),4.06-3.96(m,3H),3.83-3.78(m,1H),3.60-3.50(m,1H),3.41(s,3H),3.20-3.08(m,2H).

[0344] Example 19. Synthesis of Compound 150: N-[(1S)-1-Cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]azetidine-3-carboxamide

Chemical formula

Chemical formula

Chemical Structure

[0345] To a 50 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}azetidine-1-carboxylate (90 mg, 0.21 mmol, 1.0 eq), ACN (3 mL), and TsOH·H2O (119 mg, 0.63 mmol, 3.0 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by preparative HPLC under the following conditions: column, Atlantis Prep T3 OBD column, 19×150 mm, 5 μm, mobile phase, water (0.05% NH3·H2O) and ACN (25% phase B, to 50% in 10 min) to give N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]azetidine-3-carboxamide (21.3 mg, 31%) as a white solid.

[0346] Analysis data LCMS(ES, m / z): [M + H] + : 331.

[0347] 1H NMR(400 MHz, DMSO-d6) δ 8.66(d, J = 7.9 Hz, 1H), 7.96 - 7.86(m, 4H), 7.73(d, J = 7.9 Hz, 2H), 7.44(d, J = 8.0 Hz, 2H), 5.01(q, J = 7.8 Hz, 1H), 3.61(t, J = 7.0 Hz, 1H), 3.50(t, J = 7.0 Hz, 1H), 3.45 - 3.35(m, 3H), 3.20 - 3.08(m, 2H).

[0348] Example 20. Synthesis of Compound 152: (S)-N-(1-Cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate [Chemical formula] Synthesis of tert-butyl 3-{[(1S)-1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]carbamoyl}azetidine-1-carboxylate [Chemical formula] To a stirred solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (50 mg, 0.24 mmol, 1.0 equiv), (2S)-2-amino-3-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile (89 mg, 0.29 mmol, 1.2 equiv), and DIEA (96 mg, 0.74 mmol, 3.0 equiv) in DCM (5 mL) was added HATU (113 mg, 0.29 mmol, 1.2 equiv) portionwise at 0 °C in several portions. The resulting mixture was stirred at room temperature for an additional 2 h. The mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography eluting with PE / THF (1:1) to afford tert-butyl 3-{[(1S)-1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]carbamoyl}azetidine-1-carboxylate (80 mg, 66.7%) as a white solid. LCMS (ES, m / z): [M+H] + : 483. (S)-N-(1-Cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate synthesis [Chemical formula]

[0349] To a 50 mL round-bottom flask, tert-butyl 3-{[(1S)-1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]carbamoyl}azetidine-1-carboxylate (80 mg, 0.16 mmol, 1.0 equiv), TsOH (86 mg, 0.49 mmol, 3.0 equiv) and ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g; mobile phase, MeCN / H2O (0.1% TFA), gradient of 10% - 80% in 10 min; detector, UV 254 nm. The target fraction was lyophilized to give (S)-N-(1-cyano-2-(5-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (20.5 mg, 25%) as a white solid.

[0350] Analysis data LCMS(ES,m / z):[M-TFA+H] + :383.1

[0351] 1 H NMR(400MHz,DMSO-d6) δ 9.13(d,J=7.6Hz,1H),8.74(brs,2H),7.52(s,1H),7.41(d,J=3.6Hz,1H),7.37-7.32(m,2H),7.05(d,J=3.6Hz,1H),5.04(q,J=7.4Hz,1H),4.08-3.99(m,3H),3.93-3.89(m,1H),3.64-3.56(m,1H),3.42-3.37(m,4H),3.29-3.26(m,1H).

[0352] Example 21. Synthesis of Compound 153: N-[(1S)-1-Cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]azetidine-3-carboxamide trifluoroacetate

Chem.

[0353] To a stirred solution of tert-butyl 3-{[(1S)-1-cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]carbamoyl}azetidine-1-carboxylate (80 mg, 0.18 mmol, 1.0 equiv) in ACN (3 mL) was added TsOH (94 mg, 0.54 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: Kinetex EVO C18 column, 21.2×150, 5 μm, mobile phase, water (0.1% TFA) and ACN (10% phase B, 50% in 15 min), detector, UV254 nm. The target fraction was lyophilized to give N-[(1S)-1-cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]azetidine-3-carboxamide trifluoroacetate (20 mg, 24%) as a white solid.

[0354] 1 H NMR (300 MHz, DMSO-d6) δ 9.14 (d, J = 7.7 Hz, 1H), 8.77 (brs, 2H), 7.89 - 7.79 (m, 4H), 7.63 (d, J = 3.7 Hz, 1H), 7.11 (d, J = 3.7 Hz, 1H), 5.06 (q, J = 7.8 Hz, 1H), 4.12 - 3.95 (m, 3H), 3.89 (dd, J = 10.5, 7.2 Hz, 1H), 3.68 - 3.51 (m, 1H), 3.47 - 3.34 (m, 2H).

[0355] LCMS (ES) [M+1] + m / z: 337.

[0356] Example 22. Synthesis of Compound 154: (S)-N-(1-Cyano-2-(5-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Chemical Structure

Chemical Structure

Chemical Structure

[0357] To a stirred solution of tert-butyl 3-{[(1S)-1-cyano-2-{5-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]thiophen-2-yl}ethyl]carbamoyl}azetidine-1-carboxylate (90 mg, 0.18 mmol, 1.0 eq) in ACN (2 mL) was added TsOH (95 mg, 0.55 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: column, Kinetex EVO C18 column, 21.2×150 mm, 5 um, mobile phase, water (0.1% TFA) and ACN (10% phase B, to 50% in 15 min), detector, UV254 nm. The target fraction was lyophilized to give (S)-N-(1-cyano-2-(5-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (20 mg, 28%) as a white solid.

[0358] 1 H NMR (300 MHz, DMSO-d6) δ 9.17 (d, J = 7.6 Hz, 1H), 8.81 (brs, 2H), 7.53 (t, J = 1.1 Hz, 1H), 7.41 (d, J = 3.6 Hz, 1H), 7.41 - 7.29 (m, 2H), 7.05 (d, J = 3.6 Hz, 1H), 5.04 (q, J = 7.4 Hz, 1H), 4.12 - 4.00 (m, 3H), 3.91 (t, J = 8.9 Hz, 1H), 3.66 - 3.54 (m, 1H), 3.44 - 3.23 (m, 2H). LCMS (ES) [M - TFA + H] + m / z: 386

[0359] Example 23. Synthesis of Compound 155: (S)-N-(1-Cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Chemical Structure

Chemical Structure

Chemical Structure

[0360] To a 25 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}azetidine-1-carboxylate (90 mg, 0.18 mmol, 1.0 equiv), ACN (3 mL), and TsOH (94 mg, 0.54 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g; mobile phase, MeCN / H2O (0.1% TFA), gradient from 10% to 50% in 10 min; detector, UV 254 nm. Thereby, (S)-N-(1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (22.9 mg, 24.8%) was obtained as a white solid.

[0361] Analysis data LCMS (ES, m / z): [M-TFA+H] + : 395.2

[0362] 1 H NMR (400 MHz, DMSO-d6) δ 9.16 - 9.09 (m, 1H), 8.69 (brs, 2H), 7.67 (d, J = 1.8 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.54 - 7.46 (m, 2H), 7.42 (d, J = 8.4 Hz, 1H), 5.09 (q, J = 7.7 Hz, 1H), 4.05 - 3.96 (m, 3H), 3.89 - 3.84 (m, 1H), 3.60 - 3.52 (m, 1H), 3.41 (s, 3H), 3.25 - 3.13 (m, 2H).

[0363] Example 24. Synthesis of Compound 156: (S)-N-(1-Cyano-2-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Chem.

[0364] To a stirred solution of tert-butyl 3-{[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}azetidine-1-carboxylate (100 mg, 0.23 mmol, 1.0 equiv) in ACN (2 mL) was added TsOH (115 mg, 0.69 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: column, Kinetex EVO C18 column, 21.2×150 mm, 5 μm, mobile phase, water (0.1% TFA), and ACN (10% phase B, 50% in 15 min), detector, UV254 nm. The target fraction was lyophilized to give (S)-N-(1-cyano-2-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (25 mg, 25%).

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 7.7 Hz, 1H), 8.75 (brs, 2H), 7.95 (s, 4H), 7.69 (dd, J = 11.4, 1.8 Hz, 1H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 5.10 (q, J = 7.6 Hz, 1H), 4.09 - 3.94 (m, 3H), 3.85 (dd, J = 10.5, 7.2 Hz, 1H), 3.63 - 3.50 (m, 1H), 3.29 - 3.13 (m, 2H). LCMS (ES) [M+1] + m / z: 349

[0366] Example 25. Synthesis of Compound 157: (S)-N-(1-Cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate

Chemical Structure

Chemical Structure

Chemical Structure

[0367] To a 25 mL round-bottom flask were added tert-butyl 3-{[(1S)-1-cyano-2-{2-fluoro-4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}azetidine-1-carboxylate (100 mg, 0.20 mmol, 1.0 equiv) and TsOH (104 mg, 0.60 mmol, 3.0 equiv) in ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g, mobile phase, MeCN / H2O (0.1% TFA), gradient of 10% - 80% in 10 min, detector, UV254 nm. This gave (S)-N-(1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)azetidine-3-carboxamide 2,2,2-trifluoroacetate (20.0 mg, 20%) as a white solid.

[0368] LCMS(ES,m / z):[M-TFA+H] + :398.3

[0369] 1 H NMR(400MHz,DMSO-d6) δ 9.15(d,J=7.7Hz,1H),8.74(brs,2H),7.67(d,J=1.9Hz,1H),7.65-7.55(m,2H),7.54-7.46(m,2H),7.42(d,J=8.3Hz,1H),5.09(q,J=7.6Hz,1H),4.09-3.95(m,3H),3.89-3.84(m,1H),3.61-3.52(m,1H),3.25-3.13(m,2H).

[0370] Example 26. Synthesis of Compound 187: (2S,3aS,6aR)-N-[(1S)-1-Cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0371] To a 50 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (100 mg, 0.18 mmol, 1.0 eq), TsOH (97 mg, 0.56 mmol, 3.0 eq), and ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g; mobile phase, MeCN / H2O (0.1% NH3·H2O), 10% - 80% gradient over 10 min; detector, UV254 nm. This gave (2S,3aS,6aR)-N-[(1S)-1-cyano-2-[4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (27.1 mg, 33.4%) as a white solid.

[0372] Analysis data LCMS(ES,m / z):[M+H] + :433.2

[0373] 1 H NMR(400MHz,DMSO-d6) δ 8.53(d,J=8.4Hz,1H),7.66(d,J=7.9Hz,2H),7.58(s,1H),7.43-7.39(m,4H),5.02(q,J=7.8Hz,1H),3.85-3.79(m,1H),3.67-3.56(m,2H),3.49-3.32(m,6H),3.25-3.19(m,3H),2.73-2.66(m,1H),2.16-2.04(m,1H),1.47-1.41(m,1H).

[0374] Example 27. Synthesis of Compound 183: (2S,3aS,6aR)-N-[(1S)-1-Cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0375] To a 50 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (100 mg, 0.21 mmol, 1.0 equiv), ACN (3 mL), and TsOH·H2O (117 mg, 0.62 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by preparative HPLC under the following conditions: column, Atlantis Prep T3 OBD column, 19×150 mm, 5 μm, mobile phase, water (0.05% NH3·H2O) and ACN (25% phase B, up to 50% in 10 min) to give (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{4'-cyano-[1,1'-biphenyl]-4-yl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (21.7 mg, 27%) as a white solid.

[0376] Analysis data LCMS(ES,m / z):[M+H] + : 387.

[0377] 1 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 5.03 (q, J = 7.9 Hz, 1H), 3.85 - 3.79 (m, 1H), 3.63 - 3.56 (m, 2H), 3.48 - 3.42 (m, 2H), 3.35 - 3.33 (m, 1H), 3.24 - 3.19 (m, 3H), 2.70 - 2.64 (m, 1H), 2.12 - 2.05 (m, 1H), 1.44 - 1.37 (m, 1H).

[0378] Example 28. Synthesis of Compound 300: (2S,3aS,6aR)-N-((S)-1-Cyano-2-(4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0379] To a 25 mL round-bottom flask, (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (85 mg, 0.15 mmol, 1.0 equiv), ACN (3 mL), and TsOH (82 mg, 0.47 mmol, 3.0 equiv) were sequentially added at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g, mobile phase, MeCN / H2O (0.1% NH3.H2O), 10% - 50% gradient over 10 minutes; detector, UV254 nm. This gave (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (13.9 mg, 20%) as a white solid.

[0380] Analysis data LCMS(ES,m / z):[M+H] + :436.5

[0381] 1 H NMR(400MHz,DMSO-d6) δ 8.53(d,J=8.4Hz,1H),7.69-7.62(m,2H),7.58(t,J=1.1Hz,1H),7.46-7.36(m,4H),5.02(q,J=7.8Hz,1H),3.86-3.78(m,1H),3.64(dd,J=9.0,2.0Hz,1H),3.59(t,J=7.6Hz,1H),3.52-3.34(m,2H),3.38(dd,J=8.8,3.5Hz,1H),3.19(d,J=7.7Hz,2H),2.76-2.67(m,1H),2.14-2.06(m,1H),1.47-1.41(m,1H).

[0382] Example 29. Synthesis of Compound 192: (2S,3aS,6aR)-N-[(1S)-1-Cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0383] To a 25 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (90 mg, 0.16 mmol, 1.0 equiv), TsOH (86 mg, 0.50 mmol, 3.0 equiv), and ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18 - 120 g, mobile phase, MeCN / H2O (0.1% NH3.H2O), gradient from 10% to 50% in 10 minutes, detector, UV 254 nm. This gave (2S,3aS,6aR)-N-[(1S)-1-cyano-2-[5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (19.5 mg, 26.6%) as a white solid.

[0384] Analysis data LCMS(ES,m / z):[M+H] + : 439.2

[0385] 1 H NMR(400MHz,DMSO-d6) δ 8.62(d,J=8.5Hz,1H),7.53(s,1H),7.40(d,J=3.7Hz,1H),7.36 - 7.33(m,2H),7.02(d,J=3.6Hz,1H),5.01(q,J=7.7Hz,1H),3.85(t,J=6.2Hz,1H),3.70(d,J=9.0Hz,1H),3.64(t,J=7.7Hz,1H),3.51 - 3.36(m,8H),2.75 - 2.66(m,1H),2.17 - 2.10(m,1H),1.58 - 1.52(m,1H).

[0386] Example 30. Synthesis of Compound 193: (2S,3aS,6aR)-N-[(1S)-1-Cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0387] To a 25 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (90 mg, 0.18 mmol, 1.0 equiv), TsOH (94 mg, 0.54 mmol, 3.0 equiv), and ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g, mobile phase, MeCN / H2O (0.1% NH3·H2O), 10% to 50% gradient over 10 min; detector, UV254 nm. Thereby, (2S,3aS,6aR)-N-[(1S)-1-cyano-2-[5-(4-cyanophenyl)thiophen-2-yl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (14.7 mg, 20.5%) was obtained as a white solid.

[0388] Analysis data LCMS(ES,m / z):[M+H] + :393.2

[0389] 1 H NMR(400MHz,DMSO-d6) δ 8.62(d,J=8.5Hz,1H),7.87-7.80(m,4H),7.61(d,J=3.7Hz,1H),7.09(d,J=3.7Hz,1H),5.03(q,J=7.7Hz,1H),3.84(t,J=7.2Hz,1H),3.71-3.55(m,2H),3.51-3.34(m,5H),3.31-3.24(m,1H),2.75-2.66(m,1H),2.18-2.06(m,1H),1.55-1.48(m,1H).

[0390] Example 31. Synthesis of Compound 301: (2S,3aS,6aR)-N-((S)-1-Cyano-2-(5-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)thiophen-2-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

Chem.

Chem.

[0391] To a 25 mL round-bottom flask, (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{5-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]thiophen-2-yl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (80 mg, 0.15 mmol, 1.0 equiv) and TsOH (76 mg, 0.44 mmol, 3.0 equiv) in ACN (3 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN / H2O (0.1% NH3.H2O), gradient from 10% to 80% in 10 min; detector, UV 254 nm. Thereby, (2S,3aS,6aR)-N-((S)-1-cyano-2-(5-(3-(methyl-d3)-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)thiophen-2-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (16.0 mg, 25%) was obtained as a white solid.

[0392] Analysis data LCMS(ES,m / z):[M+H] + : 442.2

[0393] 1 H NMR(400MHz,DMSO-d6) δ 8.61(d,J=8.5Hz,1H),7.53(d,J=1.6Hz,1H),7.39(d,J=3.6Hz,1H),7.38 - 7.33(d,J=2.3Hz,2H),7.02(d,J=3.6Hz,1H),5.01(q,J=7.7Hz,1H),3.87 - 3.82(m,1H),3.70(dd,J=9.0,2.0Hz,1H),3.67 - 3.61(m,1H),3.53 - 3.32(m,5H),2.76 - 2.70(m,1H),2.20 - 2.06(m,1H),1.58 - 1.52(m,1H).

[0394] Example 32. Synthesis of Compound 195: (2S,3aS,6aR)-N-((S)-1-cyano-2-(2-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical Structure

[0395] To a 25 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (110 mg, 0.20 mmol, 1.0 equiv), TsOH (103 mg, 0.60 mmol, 3.0 equiv), and ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g, mobile phase, MeCN / H2O (0.1% NH3·H2O), gradient of 10% - 50% in 10 min; detector, UV 254 nm. Thereby, (2S,3aS,6aR)-N-[(1S)-1-cyano-2-[2-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl]-hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (18.9 mg, 21%) was obtained as a white solid.

[0396] Analysis data LCMS(ES,m / z):[M+H] + :451.2

[0397] 1 H NMR(400MHz,DMSO-d6) δ 8.63(d,J=8.4Hz,1H),7.66(s,1H),7.63-7.52(m,2H),7.52-7.43(m,2H),7.41(d,J=8.3Hz,1H),5.05(q,J=8.0Hz,1H),3.86-3.80(m,1H),3.66(d,J=9.3Hz,1H),3.63-3.58(m,1H),3.50-3.42(m,2H),3.41(s,3H),3.36(dd,J=8.8,3.5Hz,1H),3.30-3.16(m,3H),2.75-2.66(m,1H),2.14-2.06(m,1H),1.51-1.43(m,1H).

[0398] Example 33. Synthesis of Compound 302: (2S,3aS,6aR)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical formula

Chem.

Chem.

[0399] To a 25 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (100 mg, 0.19 mmol, 1.0 eq), TsOH (102 mg, 0.59 mmol, 3.0 eq), and ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18-120 g; mobile phase, MeCN / H2O (0.1% NH3·H2O), gradient from 10% to 50% in 10 min; detector, UV 254 nm. Thereby, (2S,3aS,6aR)-N-((S)-1-cyano-2-(4'-cyano-3-fluoro-[1,1'-biphenyl]-4-yl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide (15.1 mg, 18.8%) was obtained as a white solid.

[0400] Analysis data LCMS(ES,m / z):[M+H] + :405.2

[0401] 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=8.4Hz,1H),7.96-7.92(m,4H),7.66(dd,J=11.3,1.8Hz,1H),7.60(dd,J=7.9,1.8Hz,1H),7.51(t,J=7.9Hz,1H),5.06(q,J=7.9Hz,1H),3.86-3.78(m,1H),3.68-3.56(m,2H),3.50-3.39(m,2H),3.34-3.25(m,3H),2.73-2.67(m,1H),2.15-2.05(m,1H),1.54-1.40(m,1H).

[0402] Example 34. Synthesis of Compound 303: (2S,3aS,6aR)-N-((S)-1-cyano-2-(2-fluoro-4-(3-(methyl-d3)-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)hexahydro-1H-furo[3,4-b]pyrrole-2-carboxamide

Chemical formula

Chem.

Chem.

[0403] To a 25 mL round-bottom flask were added (2S,3aS,6aR)-2-{[(1S)-1-cyano-2-{2-fluoro-4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]carbamoyl}-hexahydrofuro[3,4-b]pyrrole-1-carboxylic acid tert-butyl (85 mg, 0.15 mmol, 1.0 equiv) and TsOH (79 mg, 0.46 mmol, 3.0 equiv) in ACN (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel - 120 g; mobile phase, MeCN / H2O (0.1% NH3·H2O), 10% - 80% gradient in 10 min; detector, UV 254 nm. Thereby, (2S,3aS,6aR)-N-[(1S)-1-cyano-2-{2-fluoro-4-[3-(2H3)methyl-2-oxo-1,3-benzoxazol-5-yl]phenyl}ethyl]-hexahydro-1H-furo[3,4-b]pyrrole- carboxamide (19.0 mg, 27%) was obtained as a white solid.

[0404] Analysis data LCMS(ES,m / z):[M+H] + :454.2

[0405] 1 H NMR(400MHz,DMSO-d6) δ 8.63(d,J=8.4Hz,1H),7.66(d,J=1.9Hz,1H),7.59(dd,J=11.6,1.8Hz,1H),7.54(dd,J=7.9,1.8Hz,1H),7.51-7.43(m,2H),7.41(d,J=8.3Hz,1H),5.05(q,J=8.0Hz,1H),3.83(t,J=6.8Hz,1H),3.70-3.54(m,2H),3.49-3.41(m,2H),3.36(dd,J=8.8,3.5Hz,1H),3.32--3.17(m,3H),2.74-2.66(m,1H),2.14-2.06(m,1H),1.54-1.44(m,1H).

[0406] Example 35. Synthesis of Compound 304: (2S)-N-(1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide [Chemical formula] Synthesis of 3-(4-Bromo-3-fluorophenyl)-2-((diphenylmethylene)amino)propanenitrile [Chemical formula] To a 250 mL round-bottom flask, 2-[(diphenylmethylidene)amino]acetonitrile (5 g, 22.70 mmol, 1.0 equiv), 1-bromo-4-(bromomethyl)-2-fluorobenzene (6.08 g, 22.70 mmol, 1.0 equiv), DCM (100 mL), and BnMe3NCl (420 mg, 2.27 mmol, 0.1 equiv) were sequentially added at room temperature. Subsequently, NaOH (1.82 g, 45.40 mmol, 2.0 equiv) in 10 mL of H2O was added. The mixture was stirred at 40 °C for 48 h. The reaction was diluted with water (100 mL) and extracted with dichloromethane (100 mL × 1), and dried over anhydrous sodium sulfate. It was filtered, and the filtrate was purified by silica gel column using ethyl acetate / petroleum ether (5%). Thereby, 3-(4-bromo-3-fluorophenyl)-2-((diphenylmethylene)amino)propanenitrile (5.3 g, 57%) was obtained as a yellow oil. LCMS (ES, m / z): [M+H] + : 407. Synthesis of 2-((diphenylmethylene)amino)-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)propanenitrile [Chemical formula]

[0407] To a 50 mL round-bottom flask, 3-(4-bromo-3-fluorophenyl)-2-((diphenylmethylene)amino)propanenitrile (1 g, 2.45 mmol, 1.0 equiv), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (743 mg, 2.70 mmol, 1.1 equiv), K2CO3 (679 mg, 4.91 mmol, 2.0 equiv), dioxane (20 mL), H2O (2 mL), and Pd(dppf)Cl2 (90 mg, 0.12 mmol, 0.05 equiv) were added sequentially. The mixture was heated to 90 °C under a nitrogen gas atmosphere and stirred for 4 h. The reaction was cooled to room temperature, concentrated to remove the solvent, and the residue was purified by silica gel column using ethyl acetate / petroleum ether (1:3). Thereby, 2-((diphenylmethylene)amino)-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (1.0 g, 85%) was obtained as a yellow solid. LCMS(ES,m / z):[M+H] + : 476. Synthesis of 2-amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile

Chemical Structure

[0408] A solution of 2-((diphenylmethylene)amino)-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (1 g, 2.10 mmol, 1.0 eq) in THF (50 mL) was added dropwise with HCl (3 N) (3 mL) at room temperature. The reaction mixture was stirred for 3 h. The reaction mixture was diluted with NaHCO3 (aqueous solution) (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 2-Amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)propanenitrile (540 mg, 82%) was obtained as a yellow oil and used in the next step without further purification. LCMS (ES, m / z): [M+H] + : 312. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[3-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

Chemical Structure

[0409] To a stirred mixture of 2-amino-3-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)propanenitrile (112 mg, 0.36 mmol, 1.1 equiv), (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (80 mg, 0.33 mmol, 1.0 equiv), and DIEA (126 mg, 0.98 mmol, 3 equiv) in DCM (5 mL) was added HATU (149 mg, 0.39 mmol, 1.2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate. Filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with PE / THF (2:1) to give tert-butyl (2S)-2-({1-cyano-2-[3-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (130 mg, 74%) as a pale yellow oil. LCMS (ES, m / z): [M+H] + : 539. Synthesis of (2S)-N-(1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

Chemical Structure

[0410] To a 50 mL round-bottom flask were added (2S)-2-({1-cyano-2-[3-fluoro-4-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)phenyl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl (60 mg, 0.11 mmol, 1.0 equiv), ACN (3 mL), and TsOH·H2O (64 mg, 0.33 mmol, 3.0 equiv) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction solution was purified by preparative HPLC under the following conditions: column, Atlantis Prep T3 OBD column, 19×150 mm, 5 μm; mobile phase, water (0.05% NH3·H2O) and ACN (from 25% to 50% in 10 min) to give (2S)-N-(1-cyano-2-(3-fluoro-4-(3-methyl-2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide (22.6 mg, 46%) as a white solid.

[0411] Analysis data LCMS (ES, m / z): [M+H] + : 439.

[0412] 1 1H NMR (400 MHz, DMSO-d6) δ 8.62 (t, J = 8.1 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.34 - 7.17 (m, 3H), 5.12 - 4.98 (m, 1H), 4.05 - 3.80 (m, 2H), 3.78 - 3.54 (m, 1H), 3.38 (s, 3H), 3.27 - 3.19 (m, 2H), 3.14 - 3.01 (m, 1H), 2.84 - 2.54 (m, 3H), 1.79 - 1.70 (m, 2H).

[0413] Example 36. Synthesis of Compound 305: (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamide

Chem.

Chem.

Chemical Structure

[0414] To a stirred solution of methyl 5-bromo-3-fluorothiophene-2-carboxylate (2 g, 8.37 mmol, 1.0 equiv) in DCM (40 mL), DIBAL-H (1 M in hexanes) (25.1 mL, 25.10 mmol, 3.0 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was quenched with aqueous potassium sodium tartrate (50 mL) at 0 °C. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (12:1) to afford (5-bromo-3-fluorothiophen-2-yl)methanol (1.4 g, 79.2%) as a colorless oil (no MS signal). Synthesis of 5-bromo-2-(bromomethyl)-3-fluorothiophene

Chemical Structure

[0415] To a stirred solution of (5-bromo-3-fluorothiophen-2-yl)methanol (1.4 g, 6.63 mmol, 1.0 equiv) and CBr4 (3.30 g, 9.95 mmol, 1.5 equiv) in DCM (40 mL), PPh3 (2.61 g, 9.95 mmol, 1.5 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (99:1) to afford 5-bromo-2-(bromomethyl)-3-fluorothiophene (1.4 g, 77.0%) as a colorless oil (no MS signal). Synthesis of 3-(5-bromo-3-fluorothiophen-2-yl)-2-[(diphenylmethylene)amino]propanenitrile

Chemical Structure

[0416] To a stirred solution of 5-bromo-2-(bromomethyl)-3-fluorothiophene (1.3 g, 4.75 mmol, 1.0 eq) and 2-[(diphenylmethylene)amino]acetonitrile (1.05 g, 4.75 mmol, 1.0 eq) in DCM (25 mL) and H2O (2.5 mL) were added NaOH (0.38 g, 9.49 mmol, 2.0 eq) and benzyltrimethylazanium chloride (0.09 g, 0.47 mmol, 0.1 eq). The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with water (30 mL) and extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20:1) to afford 3-(5-bromo-3-fluorothiophen-2-yl)-2-[(diphenylmethylene)amino]propanenitrile (1.2 g, 61.1%) as a pale yellow solid. LCMS (ES) [[M+H]] + m / z: 413. Synthesis of 2-[(diphenylmethylene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile [Chemical formula]

[0417] A stirred solution of 3-(5-bromo-3-fluorothiophen-2-yl)-2-[(diphenylmethylene)amino]propanenitrile (1 g, 2.42 mmol, 1.0 equiv) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-one (0.73 g, 2.66 mmol, 1.1 equiv) in dioxane (15 mL) and H2O (1.5 mL) was added with K2CO3 (0.67 g, 4.84 mmol, 2.0 equiv) and Pd(dppf)Cl2 (0.18 g, 0.24 mmol, 0.1 equiv). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (5:1) to give 2-[(diphenylmethylene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile (0.7 g, 60%) as a pale yellow solid. LCMS (ES) [M+H] + m / z: 482. Synthesis of 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile

Chemical Structure

[0418] To a stirred solution of 2-[(diphenylmethylene)amino]-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile (700 mg, 1.45 mmol, 1.0 eq) in THF (35 mL) and H2O (3.5 mL) was added HCl (1.75 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with diethyl ether (30 mL×1). The aqueous layer was basified to pH 12 with NaOH (aqueous solution) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Thereby, 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile (370 mg, 80.2%) was obtained as a pale yellow solid. LCMS(ES)[M+H] + m / z: 318. Synthesis of tert-butyl (2S)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate

Chemical Structure

[0419] To a stirred solution of 2-amino-3-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]propanenitrile (99 mg, 0.31 mmol, 1.1 equiv) and (2S)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid (70 mg, 0.28 mmol, 1.0 equiv) in DCM (2 mL), DIEA (110 mg, 0.86 mmol, 3.0 equiv) and HATU (130 mg, 0.34 mmol, 1.2 equiv) were added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to afford tert-butyl (2S)-2-({1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylate (100 mg, 64.3%) as a white solid. LCMS (ES) [[M+H]] + m / z: 545. Synthesis of (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamide

Chemical Structure

[0420] (2S)-2-({1-Cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}carbamoyl)-1,4-oxazepane-4-carboxylic acid tert-butyl (90 mg, 0.16 mmol, 1.0 equiv) in ACN (3 mL) was stirred, and TsOH (85 mg, 0.50 mmol, 3.0 equiv) was added. The resulting mixture was stirred at room temperature for 3 h. The reaction solution was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (30% phase B, 40% in 7 min); detector, UV254 nm. Thereby, (2S)-N-{1-cyano-2-[3-fluoro-5-(3-methyl-2-oxo-1,3-benzoxazol-5-yl)thiophen-2-yl]ethyl}-1,4-oxazepane-2-carboxamide (30 mg, 40.8%) was obtained as a white solid. LCMS (ES) [M+H] + m / z: 445. 1 H NMR (300 MHz, DMSO-d6) δ 8.74 (dd, J = 8.4, 4.1 Hz, 1H), 7.57 - 7.55 (d, J = 2.7 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.40 - 7.34 (m, 2H), 5.06 - 4.88 (m, 1H), 4.08 - 3.87 (m, 2H), 3.80 - 3.70 (m, 1H), 3.47 - 3.35 (m, 4H), 3.30 - 3.24 (m, 1H), 3.20 - 3.06 (m, 1H), 2.88 - 2.59 (m, 3H), 1.82 - 1.70 (m, 2H).

[0421] Example 37. Synthesis of Compound 158: (S)-N-(1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)cyclohexanecarboxamide

Chemical Structure

Chemical Structure

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, wherein 【Chemical 1】 、 wherein R １ is [Chemical Formula 2] is R ２ is [Chemical Formula 3] is X １ , X ２ , and X ３ are each independently O, S, NR ３ , or CR ３ R ４ wherein Each R ３ , R ４ , and R ５ are independently H, F, Cl, Br, I, or C １ -C ６ alkyl, Each R ６ is independently H or C １ -C ６ alkyl, Each Y is independently O, S, CHR ６ , or NR ６ and m and m' are each independently an integer from 0 to 3, and the sum of m and m' is ≦ 3, each of n, n', and n'' is independently an integer from 0 to 3, and the sum of n, n', and n'' is ≦ 4, L is 【Chemical Formula 4】 is provided that (i) R １ is 【Chemical Formula 5】 and X １ is -CH ２ -, when L and R ２ together form 【Chemical Formula 6】 not (ii) R １ is 【Chemical Formula 7】 When it is the case, L and R ２ come together 【Chemical 8】 not (iii) R １ is 【Chemical Formula 9】 is, and L is 【Chemical Formula 10】 When it is the case, R ２ is 【Chemical Formula 11】 not (iv) R １ is 【Chemical Formula 12】 is, and L is 【Chemical 13】 In the case where it is, R ２ is 【Chemical Formula 14】 not (v) R １ is 【Chemical Formula 15】 is, and L is 【Chemical Formula 16】 When it is the case, R ２ is 【Chemical 17】 not (vi) R １ is 【Chemical 18】 is, and L is 【Chemical Formula 19】 When it is the case, R ２ is 【Chemical 20】 not (vii) R １ is 【Chemical 21】 is, and L is 【Chemical 22】 When it is, R ２ is 【Chemical 23】 not, a compound, or a pharmaceutically acceptable salt or deuterated form thereof.

2. R １ is 【Chemical 24】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

3. R １ is 【Chemical 25】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

4. R １ is 【Chemical 26】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

5. R １ is 【Chemical 27】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

6. R １ is 【Chemical 28】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

7. R １ is 【Chemical 29】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

8. R １ is 【Chemical Formula 30】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

9. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 1 and m' is 1.

10. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 1 and m' is 2.

11. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 2 and m' is 1.

12. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 1 and m' is 0.

13. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 0 and m' is 1.

14. The compound according to any one of claims 6 - 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 2 and m' is 0.

15. The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 0 and m' is 2.

16. The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt or deuterated form thereof, wherein m is 0 and m' is 0.

17. X １ The compound according to any one of claims 6 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is O.

18. X １ The compound according to any one of claims 6 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is S.

19. X １ The compound according to any one of claims 6 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein X is NH.

20. X １ is CH ２ The compound according to any one of claims 6 to 16, or a pharmaceutically acceptable salt or deuterated form thereof, wherein

21. R １ is 【Chemical 31】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

22. R １ is 【Chemical 32】 The compound according to claim 1, or a pharmaceutically acceptable salt or deuterated form thereof, which is

23. The compound according to claim 22, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the sum of n, n' and n'' is 3.

24. The compound according to claim 22, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the sum of n, n' and n'' is 2.

25. The compound according to claim 22, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the sum of n, n' and n'' is 1.

26. The compound according to claim 22, or a pharmaceutically acceptable salt or deuterated form thereof, wherein the sum of n, n' and n'' is 0.

27. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 0 and n'' is 3.

28. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 3 and n'' is 0.

29. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 3, n' is 0 and n'' is 0.

30. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 1 and n'' is 2.

31. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 2 and n'' is 1.

32. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 2, n' is 1 and n'' is 0.

33. The compound according to claim 23, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 2, n' is 0 and n'' is 1.

34. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 2, n' is 0, and n'' is 0.

35. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 2, and n'' is 0.

36. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 0, and n'' is 2.

37. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1, n' is 1, and n'' is 0.

38. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1, n' is 0, and n'' is 1.

39. The compound according to claim 24, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 1, and n'' is 1.

40. The compound according to claim 25, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 1, and n'' is 0.

41. The compound according to claim 25, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 0, n' is 0, and n'' is 1.

42. The compound according to claim 25, or a pharmaceutically acceptable salt or deuterated form thereof, wherein n is 1, n' is 0s, and n'' is 0.

43. R ２ is 【Chemical 33】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

44. R ２ is 【Chemical 34】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

45. R ２ is 【Chemical 35】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

46. R ２ is 【Chemical 36】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

47. R ２ is 【Chemical 37】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

48. R ２ is 【Chemical Formula 38】 wherein Y is O, CHR ６ , or NR ６ ; a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

49. R ６ is H or CH ３ The compound according to claim 48, wherein

50. R ２ is 【Chemical Formula 39】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

51. Y is O, CHR ６ , or NR ６ and the compound according to claim 50, or a pharmaceutically acceptable salt or deuterated form thereof.

52. R ２ is 【Chemical Formula 40】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

53. R ２ is 【Chemical Formula 41】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

54. R ２ is 【Chemical 42】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

55. R ２ is 【Chemical 43】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt or deuterated form thereof.

56. R ２ is 【Chemical 44】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

57. R ２ is 【Chemical Formula 45】 The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

58. L is 【Chemical Formula 46】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

59. R ５ The compound according to claim 58, wherein each occurrence of

60. L is 【Chemical 47】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

61. L is 【Chemical 48】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

62. L is 【Chemical 49】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

63. L is 【Chemical Formula 50】 The compound according to any one of claims 1 to 20, 22 to 48, and 53 to 55, or a pharmaceutically acceptable salt or deuterated form thereof.

64. L is 【Chemical 51】 The compound according to any one of claims 1 to 20, 22 to 48, and 53 to 55, or a pharmaceutically acceptable salt or deuterated form thereof.

65. L is 【Chemical 52】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

66. L is 【Chemical Formula 53】 The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt or deuterated form thereof.

67. The compound according to claim 1, selected from one of the compounds in Table 3.

68. The compound is 【Chemical Formula 54-1】 【Chemical Formula 54-2】 【Chemical Formula 54-3】 【Chemical 54-4】 The compound according to any one of claims 1 to 67.

69. The compound is 【Chemical Formula 55-1】 【Chemical Formula 55-2】 【Chemical Formula 55-3】 【Chemical Formula 55-4】 【Chemical Formula 55-5】 The compound according to any one of claims 1 to 67.

70. A compound of formula (II), or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 【Chemical 56】 、 In the formula, R １ is 【Chemical Formula 57-1】 【Chemical Formula 57-2】 is, Each R ２ is independently H, F, Cl, Br, I, or C １ -C ６ alkyl, L is, 【Chemical Formula 58】 is, The compound is 【Chemical Formula 59】 not, a compound, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 71** L is 【Chemical Formula 60】 is, the compound according to claim 70, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 72** L is 【Chemical Formula 61】 is, the compound according to claim 70, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 73** L is 【Chemical 62】 is, the compound according to claim 70, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 74** L is 【Chemical Formula 63】 is, the compound according to claim 70, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 75** R １ is 【Chemical Formula 64】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 76** R １ is 【Chemical Formula 65】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 77** R １ is 【Chemical Formula 66】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 78** R １ is 【Chemical Formula 67】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 79** R １ is 【Chemical Formula 68】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 80** R １ is 【Chemical Formula 69】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 81** R １ is 【Chemical 70】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 82** R １ is 【Chemical Formula 71】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 83** R １ is 【Chemical 72】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 84** R １ is 【Chemical 73】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 85** R １ is 【Chemical 74】 is, the compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof. **Claim 86** R １ is 【Chemical 75】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

87. R １ is 【Chemical 76】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

88. R １ is 【Chemical 77】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

89. R １ is 【Chemical 78】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

90. R １ is 【Chemical 79】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt thereof.

91. R １ is 【Chemical 80】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

92. R １ is 【Chemical Figure 81】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

93. R １ is 【Chemical Formula 82】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

94. R １ is 【Chemical 83】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

95. R １ is 【Chemical Formula 84】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

96. R １ is 【Chemical 85】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

97. R １ is 【Chemical 86】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

98. R １ is 【Chemical 87】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

99. R １ is 【Chemical 88】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

100. R １ is 【Chemical 89】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

101. R １ is 【Chemical Formula 90】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

102. R １ is 【Chemical Formula 91】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

103. R １ is 【Chemical Formula 92】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

104. R １ is 【Chemical Formula 93】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

105. R １ is 【Chemical Formula 94】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

106. R １ is 【Chemical Formula 95】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

107. R １ is 【Chemical Formula 96】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

108. R １ is 【Chemical 97】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

109. R １ is 【Chemical Formula 98】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

110. R １ is 【Chemical Formula 99】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

111. R １ is 【Chemical 100】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

112. R １ is 【Chemical 101】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

113. R １ is 【Chemical 102】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

114. R １ is 【Chemical 103】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

115. R １ is 【Chemical Formula 104】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

116. R １ is 【Chemical 105】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

117. R １ is 【Chemical 106】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

118. R １ is 【Chemical 107】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

119. R １ is 【Chemical 108】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

120. R １ is 【Chemical 109】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

121. R １ is 【Chemical 110】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

122. R １ is 【Chemical 111】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

123. R １ is 【Chemical 112】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

124. R １ is 【Chemical 113】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

125. R １ is 【Chemical 114】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

126. R １ is 【Chemical 115】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

127. R １ is 【Chemical 116】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

128. R １ is 【Chemical 117】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

129. R １ is 【Chemical 118】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

130. R １ is 【Chemical 119】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

131. R １ is 【Chemical 120】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

132. R １ is 【Chemical 121】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

133. R １ is 【Chemical 122】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

134. R １ is 【Chemical 123】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

135. R １ is 【Chemical 124】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

136. R １ is 【Chemical Formula 125】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

137. R １ is 【Chemical 126】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

138. R １ is 【Chemical 127】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

139. R １ is 【Chemical 128】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

140. R １ is 【Chemical 129】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

141. R １ is 【Chemical 130】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

142. R １ is 【Chemical Formula 131】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

143. R １ is 【Chemical 132】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

144. R １ is 【Chemical 133】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

145. R １ is 【Chemical 134】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

146. R １ is 【Chemical 135】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

147. R １ is 【Chemical 136】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

148. R １ is 【Chemical 137】 The compound according to any one of claims 70 to 74, or a pharmaceutically acceptable salt or deuterated form thereof.

149. The compound is 【Chemical 138-1】 【Chemical 138-2】 【Chemical 138-3】 【Chemical 138-4】 [Chemical 138-5] 【Chemical 138-6】 [[Chemical 138-7]] The compound according to any one of claims 70 to 148, or a pharmaceutically acceptable salt or deuterated form thereof.

150. The compound is 【Chemical 139-1】 【Chemical 139-2】 【Chemical 139-3】 【Chemical 139-4】 【Chemical 139-5】 [Chemical 139-6] 【Chemical 139-7】 【Chemical 139-8】 【Chemical 139-9】 The compound according to any one of claims 70 to 148, or a pharmaceutically acceptable salt or deuterated form thereof.

151. A compound of formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, wherein: 【Chemical 140】 、 In the formula, R １ is 【Chemical 141】 wherein, Each R ２ is independently H, F, Cl, Br, I, or C １ -C ６ alkyl, L is, 【Chemical 142】 A compound, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 152** L is, 【Chemical 143】 A compound according to claim 151, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 153** L is, 【Chemical 144】 A compound according to claim 151, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 154** L is, 【Chemical 145】 A compound according to claim 153, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 155** L is, 【Chemical 146】 A compound according to claim 153, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 156** R １ is 【Chemical 147】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 157** R １ is 【Chemical 148】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 158** R １ is 【Chemical 149】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 159** R １ is 【Chemical Formula 150】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 160** R １ is 【Chemical 151】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 161** R １ is 【Chemical 152】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 162** R １ is 【Chemical 153】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 163** R １ is 【Chemical 154】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 164** R １ is 【Chemical 155】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 165** R １ is 【Chemical 156】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 166** R １ is 【Chemical 157】 A compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof, wherein **Claim 167** R １ is 【Chemical 158】 The compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof.

168. R １ is 【Chemical 159】 The compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof.

169. R １ is 【Chemical 160】 The compound according to any one of claims 151 to 155, or a pharmaceutically acceptable salt or deuterated form thereof.

170. The compound is 【Chemical Formula 161-1】 【Chemical 161-2】 【Chemical 161-3】 The compound according to any one of claims 151 to 169, or a pharmaceutically acceptable salt or deuterated form thereof.

171. The compound is 【Chemical Formula 162-1】 【Chemical 162-2】 ​ The compound according to any one of claims 151 to 169, or a pharmaceutically acceptable salt or deuterated form thereof.

172. A compound of formula (I-I), or a pharmaceutically acceptable salt or deuterated form thereof, wherein 【Chemical 163】 、 In the formula, R １ is 【Chemical 164】 is R ２ is 【Chemical 165】 is X １ , X ２ , and X ３ are independently O, S, NR ３ , or CR ３ R ４ wherein Each R ３ , R ４ , and R ５ is independently H, F, Cl, Br, I, or C １ -C ６ alkyl, Each R ６ is independently H or C １ -C ６ alkyl, Each Y is independently O, S, CHR ６ , or NR ６ and m and m' are each independently an integer from 0 to 3, and the sum of m and m' is ≦ 3, L is 【Chemical 166】 is provided that the compound is 【Chemical 167】 not a compound, or a pharmaceutically acceptable salt or deuterated form thereof.

173. The following chemical structure: 【Chemical 168】 The compound according to claim 172 having formula (IA-1), or a pharmaceutically acceptable salt or deuterated form thereof.

174. The following chemical structure: 【Chemical 169】 The compound according to claim 172 having formula (IB-1), or a pharmaceutically acceptable salt or deuterated form thereof.

175. The following chemical structure: 【Chemical 170】 Having formula (IC-1), wherein at least one R ５ is F, a compound according to claim 172, or a pharmaceutically acceptable salt or deuterated form thereof.

176. The following chemical structure: 【Chemical 171】 Having formula (ID-1), In the formula, at least one R ５ is F, the compound according to claim 172, or a pharmaceutically acceptable salt or deuterated form thereof.

177. R １ is 【Chemical 172】 The compound according to claim 172, or a pharmaceutically acceptable salt or deuterated form thereof.

178. R １ is 【Chemical 173】 The compound according to claim 177, or a pharmaceutically acceptable salt or deuterated form thereof.

179. R １ is 【Chemical 174】 The compound according to claim 177, or a pharmaceutically acceptable salt or deuterated form thereof.

180. R １ is 【Chemical 175】 The compound according to claim 177, or a pharmaceutically acceptable salt or deuterated form thereof.

181. R １ is 【Chemical 176】 The compound according to claim 177, or a pharmaceutically acceptable salt or deuterated form thereof.

182. R １ is 【Chemical 177】 The compound according to claim 177, or a pharmaceutically acceptable salt or deuterated form thereof.

183. R １ is 【Chemical 178】 The compound according to any one of claims 176 to 178, or a pharmaceutically acceptable salt or deuterated form thereof.

184. R １ is 【Chemical 179】 The compound according to any one of claims 176 to 178, or a pharmaceutically acceptable salt or deuterated form thereof.

185. R １ is 【Chemical Formula 180】 The compound according to any one of claims 176 to 178, or a pharmaceutically acceptable salt or deuterated form thereof.

186. R １ is 【Chemical 181】 The compound according to any one of claims 176 to 177 or 179, or a pharmaceutically acceptable salt or deuterated form thereof.

187. R １ is 【Chemical 182】 The compound according to any one of claims 176 to 177 or 179, or a pharmaceutically acceptable salt or deuterated form thereof.

188. R １ is 【Chemical 183】 The compound according to any one of claims 176 to 177 or 179, or a pharmaceutically acceptable salt or deuterated form thereof.

189. R １ is 【Chemical 184】 The compound according to any one of claims 176 to 177 or 182, or a pharmaceutically acceptable salt or deuterated form thereof.

190. The compound according to any one of claims 173 to 176, wherein m is 1 and m' is 1, or a pharmaceutically acceptable salt or deuterated form thereof.

191. The compound according to any one of claims 173 to 176, wherein m is 1 and m' is 2, or a pharmaceutically acceptable salt or deuterated form thereof.

192. The compound according to any one of claims 173 to 176, wherein m is 2 and m' is 1, or a pharmaceutically acceptable salt or deuterated form thereof.

193. The compound according to any one of claims 173 to 176, wherein m is 1 and m' is 0, or a pharmaceutically acceptable salt or deuterated form thereof.

194. The compound according to any one of claims 173 to 176, wherein m is 0 and m' is 1, or a pharmaceutically acceptable salt or deuterated form thereof.

195. The compound according to any one of claims 173 to 176, wherein m is 2 and m' is 0, or a pharmaceutically acceptable salt or deuterated form thereof.

196. The compound according to any one of claims 173 to 176, wherein m is 0 and m' is 2, or a pharmaceutically acceptable salt or deuterated form thereof.

197. The compound according to any one of claims 173 to 176, wherein m is 0 and m' is 0, or a pharmaceutically acceptable salt or deuterated form thereof.

198. The compound according to any one of claims 173 to 176, wherein m is 2 and m' is 0, or a pharmaceutically acceptable salt or deuterated form thereof.

199. The compound according to any one of claims 173 to 176, wherein m is 3 and m' is 0, or a pharmaceutically acceptable salt or deuterated form thereof.

200. X １ which is O, a compound according to any one of claims 173 to 176 or 191 to 200, or a pharmaceutically acceptable salt or deuterated form thereof.

201. X １ which is S, a compound according to any one of claims 173 to 176 or 191 to 200, or a pharmaceutically acceptable salt or deuterated form thereof.

202. X １ The compound according to any one of claims 173 to 176 or 191 to 200, wherein X is NH, or a pharmaceutically acceptable salt or deuterated form thereof.

203. X １ is CH ２ and is a compound according to any one of claims 173 to 176 or 191 to 200, or a pharmaceutically acceptable salt or deuterated form thereof.

204. R ２ is 【Chemical 185】 The compound according to any one of claims 173 to 203, or a pharmaceutically acceptable salt or deuterated form thereof.

205. R ２ is 【Chemical 186】 The compound according to any one of claims 173 to 204, or a pharmaceutically acceptable salt or deuterated form thereof.

206. R ２ is 【Chemical 187】 The compound according to any one of claims 173 to 204, or a pharmaceutically acceptable salt or deuterated form thereof.

207. R ２ is 【Chemical 188】 The compound according to any one of claims 174 to 206, or a pharmaceutically acceptable salt or deuterated form thereof.

208. R ２ is 【Chemical 189】 The compound according to any one of claims 174 to 205, or a pharmaceutically acceptable salt or deuterated form thereof.

209. R ２ is 【Chemical 190】 The compound according to any one of claims 174 to 205, or a pharmaceutically acceptable salt or deuterated form thereof.

210. R ２ is 【Chemical 191】 The compound according to any one of claims 174 to 205, or a pharmaceutically acceptable salt or deuterated form thereof.

211. R ２ is 【Chemical 192】 The compound according to any one of claims 174 to 205, or a pharmaceutically acceptable salt or deuterated form thereof.

212. R ２ is 【Chemical 193】 The compound according to any one of claims 174 to 205, or a pharmaceutically acceptable salt thereof.

213. The compound according to any one of claims 210 to 211, wherein Y is O, or a pharmaceutically acceptable salt or deuterated form thereof.

214. R ６ is -CH ３ The compound according to any one of claims 201 to 211, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R is -CH

215. L is 【Chemical 194】 The compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

216. L is 【Chemical 195】 A compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

217. L is 【Chemical Formula 196】 A compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

218. L is 【Chemical 197】 A compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

219. L is 【Chemical Formula 198】 A compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

220. L is 【Chemical 199】 A compound according to any one of claims 174 to 176 or 177 to 214, or a pharmaceutically acceptable salt or deuterated form thereof.

221. Each R ５ is H, a compound according to any one of claims 217 to 230, or a pharmaceutically acceptable salt or deuterated form thereof.

222. At least one R ５ is F, a compound according to any one of claims 217 to 230, or a pharmaceutically acceptable salt or deuterated form thereof.

223. A compound according to claim 172, or a pharmaceutically acceptable salt or deuterated form thereof, selected from one of the compounds in Table 3.

224. The compound is 【Chemical 200-1】 【Chemical 200-2】 [[Chemical 200-3]] 【Chemical 200-4】 A compound according to any one of claims 172 to 223, or a pharmaceutically acceptable salt or deuterated form thereof.

225. The compound is 【Chemical 201-1】 【Chemical 201-2】 【Chemical 201-3】 【Chemical 201-4】 【Chemical 201-5】 【Chemical 201-6】 A compound according to any one of claims 172 to 223, or a pharmaceutically acceptable salt or deuterated form thereof.

226. A compound having the following chemical formula 【Chemical 202】 or a pharmaceutically acceptable salt or deuterated form thereof.

227. A compound having the following chemical formula 【Chemical 203】 or a pharmaceutically acceptable salt or deuterated form thereof.

228. A method for treating an obstructive airway disease in a patient in need thereof, the method comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

229. The method according to claim 228, wherein the obstructive disorder of the airway includes the treatment of cough suppression including asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis (CF), bronchiectasis, sarcoidosis, alpha-1 antitrypsin (A1AT) deficiency, farmer's lung and related diseases, hypersensitivity pneumonitis, pulmonary fibrosis, complications of lung transplantation, vascular disorders and thrombotic disorders of the pulmonary vascular system, pulmonary hypertension, pulmonary hypertension caused by left heart disease, pulmonary hypertension associated with chronic lung disease, cough suppression related to inflammatory and secretory states of the airway, iatrogenic cough, drug-induced rhinitis, and acute and chronic rhinitis including vasomotor rhinitis, perennial and seasonal allergic rhinitis (hay fever) including allergic rhinitis, nasal polyposis, acute viral infections including colds, and infections caused by respiratory viruses, acute lung injury, or acute respiratory distress syndrome (ARDS).

230. The method according to claim 229, wherein the obstructive disorder of the airway is asthma.

231. The method according to claim 229, wherein the obstructive disorder of the airway is acute respiratory distress syndrome (ARDS).

232. The method according to claim 229, wherein the obstructive disorder of the airway is bronchitis.

233. The method according to claim 229, wherein the obstructive disorder of the airway is pulmonary fibrosis.

234. The method according to claim 229, wherein the obstructive disorder of the airway is emphysema.

235. The method according to claim 229, wherein the obstructive disorder of the airway is cystic fibrosis (CF).

236. The method according to claim 229, wherein the obstructive disorder of the airway is bronchiectasis.

237. The method according to claim 229, wherein the obstructive disorder of the airway is sarcoidosis.

238. The method according to claim 229, wherein the obstructive disorder of the airway is alpha-1 antitrypsin (A1AT) deficiency.

239. The method according to claim 229, wherein the obstructive disorder of the airway is farmer's lung.

240. The method according to claim 229, wherein the obstructive disorder of the airway is hypersensitivity pneumonitis.

241. The method according to claim 229, wherein the obstructive disorder of the airway is a complication of lung transplantation.

242. The method according to claim 229, wherein the obstructive disorder of the airway is the vascular disorder or thrombotic disorder of the pulmonary vascular system.

243. The method according to claim 229, wherein the obstructive disorder of the airway is pulmonary hypertension.

244. The method according to claim 229, wherein the obstructive disorder of the airway is iatrogenic cough.

245. The method according to claim 229, wherein the obstructive disorder of the airway is iatrogenic cough.

246. The method according to claim 229, wherein the obstructive disorder of the airway is acute rhinitis.

247. The method according to claim 229, wherein the obstructive disorder of the airway is chronic rhinitis.

248. The method according to claim 229, wherein the obstructive disorder of the airway is nasal polyposis.

249. The method according to claim 229, wherein the obstructive disorder of the airway is pulmonary hypertension caused by left heart disease.

250. The method according to claim 229, wherein the obstructive disorder of the airway is pulmonary hypertension associated with chronic lung disease.

251. The method according to claim 230, wherein the asthma is bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, or drug-induced asthma.

252. The method according to claim 232, wherein the bronchitis is infectious bronchitis or eosinophilic bronchitis.

253. The method according to claim 233, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis, idiopathic fibrotic alveolitis, idiopathic interstitial pneumonia, or fibrosis complicated with antitumor therapy or chronic infection.

254. The method according to claim 236, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

255. The method according to claim 236, wherein the bronchiectasis is associated with cystic fibrosis.

256. The method according to claim 243, wherein the pulmonary hypertension is pulmonary arterial hypertension.

257. A method for treating cystic fibrosis in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

258. The method according to claim 255, wherein treating comprises improving the lung function of the patient as compared to the lung function of the patient before the period of administration.

259. Improving the lung function of the patient, compared to each value of the patient before the administration period, increasing the forced expiratory volume in one second (FEV １ ), increasing the forced vital capacity (FVC) of the patient, increasing the peak expiratory flow rate (PEFR) of the patient, or increasing the forced expiratory flow of the patient by 25% to 75% of FVC (FEF （２５－７５％） ), the method according to claim 258, comprising.

260. The method according to claim 258 or 259, wherein the lung function is measured by spirometry.

261. A method for treating bronchiectasis in a patient in need thereof, the method comprising administering to the patient, over a period of administration, a composition comprising an effective amount of a compound according to any one of claims 1 to 227.

262. The method according to claim 261, wherein the bronchiectasis is non-cystic fibrosis bronchiectasis (NCFBE).

263. The method according to claim 261, wherein the bronchiectasis is associated with cystic fibrosis.

264. The method according to any one of claims 260 to 263, wherein treating comprises improving the lung function of the patient as compared to the lung function of the patient before the period of administration.

265. Improving the lung function of the patient, as compared to each value of the patient before the administration period, increases the forced expiratory volume in one second (FEV １ ), increases the forced vital capacity (FVC) of the patient, increases the peak expiratory flow rate (PEFR) of the patient, or increases the forced expiratory flow of the patient by 25% to 75% of the FVC (FEF （２５－７５％） ), the method according to claim 262, comprising.

266. The method according to claim 264 or 265, wherein the lung function is measured by spirometry.

267. The method according to any one of claims 261 to 266, wherein treating comprises reducing the rate of lung exacerbation as compared to the rate of lung exacerbation of the patient before the period of administration.

268. The method according to any one of claims 189 to 267, wherein treating comprises increasing the time to the first lung exacerbation as compared to an untreated patient.

269. The lung exacerbation is characterized by three or more of the following symptoms presented by the patient for at least 48 hours: (1) increased cough, (2) increased sputum volume or change in sputum viscosity, (3) increased purulence of sputum, (4) increased shortness of breath and / or decreased exercise tolerance, (5) fatigue and / or malaise, (6) hemoptysis, according to the method of claim 267 or 268.

270. A method for treating chronic rhinosinusitis (CRS) in a patient in need thereof, the method comprising administering to the patient, over a period of administration, a composition comprising an effective amount of a compound according to any one of claims 1 to 225.

271. The method according to claim 270, wherein the chronic rhinosinusitis is chronic rhinosinusitis without nasal polyps (CRSsNP).

272. The method according to claim 270, wherein the chronic rhinosinusitis is chronic rhinosinusitis with nasal polyps (CRSwNP).

273. The method according to any one of claims 270 to 272, wherein the chronic rhinosinusitis is refractory chronic rhinosinusitis.

274. The method according to any one of claims 270 to 273, wherein treating comprises reducing, decreasing the severity of, delaying the onset of, or eliminating one or more symptoms of CRS.

275. The method according to claim 274, wherein the one or more symptoms of CRS are selected from nasal congestion, nasal obstruction, rhinorrhea, postnasal drip, facial pressure, facial pain, facial fullness, reduced sense of smell, depression, mucosal edema, mucopurulent secretions, middle meatus obstruction, changes in the mucosa in the middle meatus natural ostium route and paranasal sinuses, or nasal discharge.

276. A method for treating hidradenitis suppurativa (HS) in a patient in need thereof, the method comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

277. The method according to claim 276, wherein the hidradenitis suppurativa (HS) is Hurley stage I.

278. The method according to claim 276, wherein the hidradenitis suppurativa (HS) is Hurley stage II.

279. The method according to claim 276, wherein the hidradenitis suppurativa (HS) is Hurley stage III.

280. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

281. The method according to claim 280, wherein the cancer is metastatic cancer.

282. The method according to claim 281, wherein the metastatic cancer is metastatic cancer from breast to lung.

283. The method according to claim 281, wherein the metastatic cancer comprises metastasis of breast cancer to the brain, bone, pancreas, lymph nodes or liver.

284. The method according to claim 281, wherein the metastatic cancer comprises metastasis of bone cancer to the lung.

285. The method according to claim 281, wherein the metastatic cancer comprises metastasis of colorectal cancer to the peritoneum, pancreas, stomach, lung, liver, kidney, or spleen.

286. The method according to claim 281, wherein the metastatic cancer comprises metastasis of gastric cancer to the mesentery, spleen, pancreas, lung, liver, adrenal gland, or ovary.

287. The method according to claim 281, wherein the metastatic cancer comprises metastasis of liver cancer to the intestine, spleen, pancreas, stomach, lung, or kidney.

288. The method according to claim 281, wherein the metastatic cancer includes metastasis of lymphoma to the kidney, ovary, liver, bladder, or spleen.

289. A method for treating lupus nephritis in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

290. A method for treating rheumatoid arthritis in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

291. A method for treating inflammatory bowel disease (IBD) in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

292. The method according to claim 291, wherein the inflammatory bowel disease (IBD) is Crohn's disease.

293. The method according to claim 291, wherein the inflammatory bowel disease (IBD) is ulcerative colitis.

294. A method for treating heart failure in a patient in need thereof, comprising administering to the patient a composition comprising an effective amount of a compound according to any one of claims 1 to 227 over a period of administration.

295. The method according to claim 294, wherein the heart failure is heart failure with preserved ejection fraction.

296. The method according to claim 294, wherein the heart failure is heart failure with reduced ejection fraction.

297. The method according to any one of claims 228 to 296, wherein the composition is administered once daily during the period of administration.

298. The method according to any one of claims 228 to 296, wherein the composition is administered twice daily during the period of administration.

299. The method according to any one of claims 228 to 296, wherein the composition is administered every other day during the period of administration.

300. The method according to any one of claims 228 to 296, wherein the composition is administered once a week during the period of administration.

301. The method according to any one of claims 228 to 300, wherein the composition is in an oral dosage form.

302. The method according to claim 301, wherein the composition is administered orally.

303. The method according to any one of claims 228 to 302, wherein the composition comprises about 10 mg to about 50 mg of the compound.

304. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 30 years.

305. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 20 years.

306. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 15 years.

307. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 10 years.

308. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 5 years.

309. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 5 years.

310. The method according to any one of claims 228 to 303, wherein the administration period is about 1 year to about 3 years.

311. The method according to any one of claims 228 to 303, wherein the administration period is about 2 years to about 10 years.

312. The method according to any one of claims 228 to 303, wherein the administration period is about 2 years to about 8 years.

313. The method according to any one of claims 228 to 303, wherein the administration period is about 2 years to about 5 years.

314. The method according to any one of claims 228 to 303, wherein the administration period is about 2 years to about 4 years.

315. The method according to any one of claims 228 to 303, wherein the administration period is about 2 years to about 3 years.

316. The method according to any one of claims 228 to 303, wherein the administration period is at least about 30 days.

317. The method according to any one of claims 228 to 303, wherein the administration period is at least about 60 days.

318. The method according to any one of claims 228 to 303, wherein the administration period is at least about 90 days.

319. The method according to any one of claims 228 to 303, wherein the administration period is at least about 4 months.

320. The method according to any one of claims 228 to 303, wherein the administration period is at least about 6 months.

321. The method according to any one of claims 228 to 303, wherein the administration period is at least about 8 months.

322. The method according to any one of claims 228 to 303, wherein the administration period is at least about 10 months.

323. The method according to any one of claims 228 to 303, wherein the administration period is at least about 1 year.

324. The method according to any one of claims 228 to 303, wherein the administration period is at least about 2 years.

325. The method according to any one of claims 228 to 303, wherein the administration period is at least about 3 years.

326. The method according to any one of claims 228 to 303, wherein the administration period is at least about 4 years.

327. The method according to any one of claims 228 to 303, wherein the administration period is at least about 5 years.

328. The method according to any one of claims 228 to 303, wherein the administration period is at least about 10 years.

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